Neuropharmacology. 2011 December; 61(7): 1109–1122. Published online 2011 April 1. doi: 10.1016/j.neuropharm.2011.03.010
There is a high degree of overlap between brain regions involved in processing natural rewards and drugs of abuse. “Non-drug” or “behavioral” addictions have become increasingly documented in the clinic, and pathologies include compulsive activities such as shopping, eating, exercising, sexual behavior, and gambling.
Like drug addiction, non-drug addictions manifest in symptoms including craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse. These alterations in behavior suggest that plasticity may be occurring in brain regions associated with drug addiction.
In this review, I summarize data demonstrating that exposure to non-drug rewards can alter neural plasticity in regions of the brain that are affected by drugs of abuse. Research suggests that there are several similarities between neuroplasticity induced by natural and drug rewards and that, depending on the reward, repeated exposure to natural rewards might induce neuroplasticity that either promotes or counteracts addictive behavior.
There are now myriad television shows documenting people who compulsively engage in behaviors that may otherwise be considered normal, but do so in a manner that has a serious negative impact on their lives and those of their families. People suffering from what may be considered “non-drug” or “behavioral” addictions are becoming increasingly documented in the clinic, and symptoms include compulsive activities such as shopping, eating, exercising, sexual behavior, gambling, and video games (Holden, 2001; Grant et al, 2006a). While the subjects of these television shows may seem like extreme and rare cases, these types of disorders are surprisingly common. Prevalence rates in the United States have been estimated at 1–2% for pathological gambling (Welte et al, 2001), 5% for compulsive sexual behavior (Schaffer and Zimmerman, 1990), 2.8% for binge-eating disorder (Hudson et al, 2007) and 5–6% for compulsive buying (Black, 2007).
Although the DSM-IV acknowledges these disorders and other “addictive” behaviors, they are currently not classified as behavioral addictions. This may be due to the fact that the DSM-IV avoids the term addiction even in reference to drugs of abuse, opting instead for the terms “abuse” and “dependence”. Within the DSM-IV, behavioral addictions are grouped under categories such as “substance-related disorders”, “eating disorders”, and “impulse control disorders not elsewhere classified” (Holden, 2001; Potenza, 2006). More recently, there has been a trend toward thinking about these non-drug addictions to be more like substance abuse and dependence (Rogers and Smit, 2000; Wang et al, 2004b; Volkow and Wise, 2005; Grant et al., 2006a; Petry, 2006; Teegarden and Bale, 2007; Deadwyler, 2010; Grant et al, 2010). In fact, non-drug addictions fit the classical definition of addiction that includes engaging in the behavior despite serious negative consequences (Holden, 2001; Hyman et al, 2006). This phenomenon has been appreciated by psychiatrists, and proposed revisions for the DSM-5 include a category of Addiction and Related Behavior ((APA), 2010). Within this category, a Behavioral Addictions category has been proposed, which would include pathological gambling and potentially internet addiction ((APA), 2010; O’Brien, 2010; Tao et al, 2010).
Like substance addictions, non-drug addictions manifest in similar psychological and behavioral patterns including craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse (Marks, 1990; Lejoyeux et al, 2000; National Institute on Drug Abuse (NIDA) et al, 2002; Potenza, 2006). Similarities between drugs and non-drug rewards can also be seen physiologically. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). This article will review preclinical evidence that natural reinforcers are capable of leading to plasticity in behavior and neurotransmission that is often reminiscent of adaptations seen following exposure to drugs of abuse, especially psychostimulants. For the sake of the present review, plasticity will be broadly defined as any adaptation in behavior or neural function, similar to the usage of the term originally described by William James (James, 1890). Synaptic plasticity will refer to an alteration at the level of the synapse, typically measured using electrophysiological methods (e.g., changes in AMPA/NMDA ratio). Neurochemical plasticity will refer to altered neurotransmission (synaptic or intracellular) measured biochemically by differences in basal or evoked levels of transmitter, receptor, or transporter, or by an enduring change in phosphorylation state of any of these molecules. Behavioral plasticity will refer to any adaptation in behavior (several examples are discussed in Section 1.1).
Neural circuits that underlie encoding of natural rewards are thought to be “hijacked” by drugs of abuse, and plasticity in these circuits is believed to be responsible for the behavioral plasticity (i.e. increased drug seeking and craving) characteristic of addiction (Kelley and Berridge, 2002; Aston-Jones and Harris, 2004; Kalivas and O’Brien, 2008; Wanat et al, 2009b). Evidence for this hijacking is seen in several forms of plasticity in brain regions known to affect motivation, executive function, and reward processing (Kalivas and O’Brien, 2008; Thomas et al, 2008; Frascella et al, 2010; Koob and Volkow, 2010; Pierce and Vanderschuren, 2010; Russo et al, 2010). Animal models have given us a snapshot of the profound changes that administration of drugs of abuse can impart. Adaptations range from altered neurotransmitter levels to altered cell morphology and changes in transcriptional activity (Robinson and Kolb, 2004; Kalivas et al, 2009; Russo et al., 2010). Several groups have also reported drugs of abuse altering synaptic plasticity in key regions of the brain implicated in drug addiction (for review, see (Winder et al, 2002; Kauer and Malenka, 2007; Luscher and Bellone, 2008; Thomas et al., 2008). The majority of the neuroadaptations described have been in regions of the mesocorticolimbic system and the extended amygdala (Grueter et al, 2006; Schramm-Sapyta et al, 2006; Kauer and Malenka, 2007; Kalivas et al., 2009; Koob and Volkow, 2010; Russo et al., 2010; Mameli et al, 2011).
Based on known roles of these regions in regulation of mood, processing of natural rewards, and motivated behavior, it is widely believed that this plasticity underlies the maladaptive changes in behavior associated with addiction. In humans, some of these changes include impaired decision making, decreased pleasure from natural rewards (anhedonia), and craving (Majewska, 1996; Bechara, 2005; O’Brien, 2005). In animal models, these altered behaviors can be studied with neurobehavioral measures following a history of drug administration, and analogous brain regions are thought to mediate these measures (Markou and Koob, 1991; Shaham et al, 2003; Bevins and Besheer, 2005; Winstanley, 2007). These measures provide the basis for preclinical testing of pharmacotherapies that may be useful in the treatment of addiction.
Recent evidence suggests that non-drug addictions may lead to neuroadaptations similar to those reported with long-term drug use. While the majority of these examples of plasticity are emerging from animal studies, reports also include examples from human studies.
In this review, we will explore the concept that natural rewards are capable of inducing neural and behavioral plasticity in ways analogous to drug addiction. Future study of this phenomenon may give us insights into behavioral addictions and promote “crossover” pharmacotherapies that could benefit both drug and non-drug addictions (Frascella et al., 2010).
1.1. Theories of behavioral plasticity and addiction
In the field of drug addiction, several theories have emerged to explain how neural and behavioral plasticity contribute to addiction. One theory is that of incentive-sensitization (Robinson and Berridge, 1993, 2001, 2008). According to this theory, in susceptible individuals, repeated drug exposure leads to a sensitization (reverse tolerance) of the incentive-motivational properties of drugs and drug-related cues. This alteration is at least in part mediated by sensitized nucleus accumbens (NAc) dopamine (DA) release following exposure to drug-related cues. Behaviorally, this is associated with increased wanting and craving of drugs when one is exposed to cues that are associated with intake (i.e. a crack pipe). In animal models, incentive sensitization can be modeled by measuring drug-seeking behaviors in response to cues paired with drug administration (Robinson and Berridge, 2008). Locomotor sensitization also occurs with repeated administration of several drugs of abuse and may be an indirect measure of incentive sensitization, although locomotor and incentive sensitization are dissociable processes (Robinson and Berridge, 2008). Notably, sensitization processes can also translate between drug and non-drug rewards (Fiorino and Phillips, 1999; Avena and Hoebel, 2003b; Robinson and Berridge, 2008). In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008).
Another theory that has been developed to explain how drug-related plasticity contributes to addiction is the opponent process theory (Solomon, 1980; Koob et al, 1989; Koob and Le Moal, 2008). Briefly, this theory of motivation states that there are two processes engaged during repeated experiences: the first involves affective or hedonic habituation, the second process is an affective or hedonic withdrawal (Solomon and Corbit, 1974). An example provided by Solomon related to opiate use, where tolerance developed to the acute hedonic effects following repeated drug exposure, and negative symptoms of withdrawal would emerge which would further motivate drug use (negative reinforcement) (Solomon, 1980). This early version of the theory was originally developed to explain behavior altered by exposure to both drug and non-drug rewards (for review, see (Solomon, 1980)). An expansion of opponent process theory is the allostatic model of brain motivational systems (Koob and Le Moal, 2001, 2008). Briefly, this model includes the opposing concepts of reward and anti-reward, while the latter involves a failure to return to a homeostatic set point, leading to negative affect and reduction in natural reward, which increases motivation to relieve this state (Koob and Le Moal, 2008). Evidence for neuroplasticity that regulates this altered affective state comes from several findings, including decreased basal NAc DA following drug withdrawal in rats (Weiss et al, 1992), decreased striatal D2 receptors in striatum and accumbens of human alcoholics and abstinent heroin addicts (Volkow et al., 2004; Zijlstra et al, 2008), and increased intracranial self-stimulation (ICSS) thresholds during cocaine withdrawal in rats (Markou and Koob, 1991). In addition to alterations in mesolimbic DA signaling, central stress systems are also recruited. A particularly robust example is increased CRF signaling in the hypothalamus, central nucleus of the amygdala, and bed nucleus of the stria terminalis following withdrawal of many drugs of abuse (Koob and Le Moal, 2008).
A third theory to describe neuroplasticity contributing to addiction is the recruitment of habit-based neurocircuitry throughout repeated drug exposure (Everitt et al, 2001; Everitt et al, 2008; Graybiel, 2008; Ostlund and Balleine, 2008; Pierce and Vanderschuren, 2010). For example, non-human primates self-administering cocaine show changes in glucose metabolism and levels of dopamine D2 receptor and dopamine transporter that initially affect the ventral striatum, but with increasing exposure expand into the dorsal striatum (Porrino et al, 2004a; Porrino et al, 2004b). This expansion “suggests that the elements of the behavioral repertoire outside of the influence of cocaine become smaller and smaller with increasing durations of exposure to drug use resulting in cocaine’s dominance over all aspects of the addict’s life” (Porrino et al., 2004a). This progressive plasticity from ventral to dorsal striatum parallels an older literature on the transition from goal- to habit-based learning (Balleine and Dickinson, 1998) and has an anatomical correlate that supports the ability of extended reward-based learning to engage progressively more dorsal aspects of the striatum (Haber et al, 2000).
2. Food Reward
Perhaps the most extensively studied reward is that of food. Food is the quintessential reward in many rodent studies and has been used as a reinforcer in procedures such as operant (self-administration) tasks, runway tests, maze learning, gambling tasks, and place conditioning (Skinner, 1930; Ettenberg and Camp, 1986; Kandel et al, 2000; Kelley, 2004; Tzschentke, 2007; Zeeb et al, 2009). In rats that were trained to press a lever to receive intravenous self-administration of drugs, highly palatable foods such as sugar and saccharin were shown to reduce self-administration of cocaine and heroin (Carroll et al, 1989; Lenoir and Ahmed, 2008), and these natural reinforcers have been demonstrated to outcompete cocaine in choice self-administration in the majority of rats tested (Lenoir et al, 2007; Cantin et al, 2010). This would suggest that sweet foods have a higher reinforcing value than cocaine, even in animals with an extensive history of drug intake (Cantin et al., 2010). While this phenomenon could appear as a weakness in current models of cocaine addiction, a minority of rats prefer cocaine to sugar or saccharin (Cantin et al., 2010). It is possible that these animals may represent a “vulnerable” population, which is more relevant to the human condition. This notion is explored more in the Discussion (Section 6.1).
Work from many laboratories has demonstrated examples of plasticity in reward-related circuits following access to palatable food. Neurobehavioral adaptations following a history of palatable food intake have been likened to those observed following drugs of abuse, prompting several scientists to propose that dysregulation of food intake may be similar to addiction (Hoebel et al, 1989; Le Magnen, 1990; Wang et al., 2004b; Volkow and Wise, 2005; Davis and Carter, 2009; Nair et al, 2009a; Corsica and Pelchat, 2010). The laboratory of Bartley Hoebel has extensive data demonstrating behavioral plasticity following a history of intermittent sugar access, which has led he and his colleagues to propose that sugar consumption that meets criteria for addiction (Avena et al, 2008). This notion is supported by the fact that several examples of plasticity seen following repeated drug exposure are also observed following intermittent access to not only sugar, but also fat. Different types of palatable food have been used to study plasticity, including high sugar, high fat, and “Western” or “Cafeteria” diets to try to model different human eating patterns.
- During repeated access to sugar, escalation of intake is observed (Colantuoni et al, 2001), a phenomenon previously associated with cocaine and heroin self-administration (Ahmed and Koob, 1998; Roberts et al, 2007). Escalation is an increase in intake that occurs during the initial phase (e.g. the first hour of a six hour session) of self-administration after a history of repeated sessions, a phenomenon thought to mimic human patterns of drug intake (Koob and Kreek, 2007).
- Following removal of sugar or fat access, withdrawal symptoms including anxiety- and depressive-like behaviors emerge (Colantuoni et al, 2002; Teegarden and Bale, 2007).
- After this period of “abstinence”, operant testing reveals “craving” and “seeking” behavior for sugar (Avena et al, 2005) or fat (Ward et al, 2007), as well as “incubation of craving” (Grimm et al, 2001; Lu et al, 2004; Grimm et al, 2005), and “relapse” (Nair et al, 2009b) following abstinence from sugar.
- In fact, when given a re-exposure to sugar after a period of abstinence, animals consume a much greater amount of sugar than during previous sessions (Avena et al., 2005). This deprivation effect was originally described for alcohol (Sinclair and Senter, 1968), and is thought to be another preclinical model of craving and relapse (McBride and Li, 1998; Spanagel and Holter, 1999).
- Finally, following intermittent exposure to a high fat diet, food-seeking was continued despite adverse consequences (Teegarden and Bale, 2007; Johnson and Kenny, 2010), which has been proposed as a animal corollary for risky acquisition of drugs seen in human addicts (Deroche-Gamonet et al, 2004).
Another indication of plasticity induced by diet is that a “cross-sensitization” of the locomotor activity between intermittent sugar intake and psychostimulants can be induced in either order of treatment (Avena and Hoebel, 2003b, a; Gosnell, 2005). Cross-sensitization is a phenomenon that occurs following previous exposure to an environmental or pharmacological agent (such as a stressor or psychostimulant, respectively) that results in an enhanced response (typically locomotor) to a different environmental or pharmacological agent (Antelman et al, 1980; O’Donnell and Miczek, 1980; Kalivas et al, 1986; Vezina et al, 1989). Sensitization processes involving psychostimulants involve mesolimbic DA neurons, and cross-sensitization is believed to occur from common mechanisms of action between two stimuli (Antelman et al., 1980; Herman et al, 1984; Kalivas and Stewart, 1991; Self and Nestler, 1995).
Cross-sensitization to psychostimulants is also seen in animals fed a high sugar/fat diet during perinatal and post-weanling periods (Shalev et al, 2010). To determine if exposure to a high fat diet could alter the “rewarding” (reinforcing) effects of a drug of abuse, Davis et al. tested animals fed a high fat diet for altered sensitivity to amphetamine using a conditioned place preference (CPP) paradigm (Davis et al, 2008). In this model, animals are first allowed to explore a multi-chamber apparatus (the pre-test) where each chamber has distinct visual, tactile, and/or olfactory cues. During conditioning sessions, the animals are confined to one of the chambers and paired with a reward (e.g. amphetamine injection or food in the chamber). These sessions are repeated and interleaved with conditioning sessions that involve pairing of another chamber of the apparatus with the control condition (e.g. saline injection or no food). The test phase is done under the same conditions as the pre-test and CPP is demonstrated when animals show a significant preference for the chamber that was paired with the drug or non-drug reward. Davis et al. found that high fat fed rats failed to develop conditioned place preference for amphetamine, suggesting a cross-tolerance between the intake of high fat food and the conditioned reinforcing effects of amphetamine (Davis et al., 2008).
- Withdrawal is a phenomenon also seen following repeated exposure to highly palatable foods. Somatic signs of withdrawal commonly associated with naloxone precipitated opiate withdrawal can be also be precipitated by naloxone or food restriction following intermittent sugar (Colantuoni et al., 2002) or a cafeteria style diet (Le Magnen, 1990).
- Elevated thresholds for brain stimulation reward, which are commonly observed following withdrawal from cocaine, alcohol, amphetamine, and nicotine (Simpson and Annau, 1977; Cassens et al, 1981; Markou and Koob, 1991; Schulteis et al, 1995; Wise and Munn, 1995; Epping-Jordan et al, 1998; Rylkova et al, 2009), are observed in rats following 40 days access to a cafeteria diet in addition to regular chow, and this effect persisted at least 14 days following withdrawal of the high fat food (Johnson and Kenny, 2010). This measure has commonly been used to describe a state of relative anhedonia characterized by lower tone of endogenous brain reward systems (Kenny, 2007; Wise, 2008; Bruijnzeel, 2009; Carlezon and Thomas, 2009) and is thought to regulate continued intake of drugs (and perhaps food) to relieve this state (a phenomenon known as negative reinforcement) (Cottone et al, 2008; Koob, 2010).
In addition to behavioral plasticity, excessive intake of certain types of food has also been associated with neurochemical plasticity. In particular, dopamine and opioid signaling appears to be susceptible to adaptations following intermittent access to high sugar or high fat foods. In the NAc, intermittent feeding episodes with access to sugar and chow increase D1 and D3 receptor content (either mRNA or protein), while decreasing D2 receptors in the NAc and dorsal striatum (Colantuoni et al., 2001; Bello et al, 2002; Spangler et al, 2004). This effect was also observed with extended access to a high fat diet in rats, with the greatest decrease in D2 occurring in the heaviest rats (Johnson and Kenny, 2010). These adaptations in accumbal and striatal dopamine receptors parallel those seen in rodents repeatedly administered cocaine or morphine (Alburges et al, 1993; Unterwald et al, 1994a; Spangler et al, 2003; Conrad et al, 2010). Further, reductions in striatal D2 receptors are also seen in human psychostimulant users and alcoholics (Volkow et al, 1990; Volkow et al, 1993; Volkow et al, 1996; Zijlstra et al., 2008), and in obese adults, where D2 content was found to negatively correlate with body mass index (Wang et al., 2004b). Endogenous opioid signaling is also affected profoundly by diet (Gosnell and Levine, 2009). Intermittent sugar or sweet/fat diet increases mu opioid receptor binding in the NAc, cingulate cortex, hippocampus and locus coeruleus (Colantuoni et al., 2001) and decreases enkephalin mRNA in NAc (Kelley et al, 2003; Spangler et al., 2004). Neurochemical plasticity in mesolimbic DA and opioid signaling has also been demonstrated to occur in the offspring of female mice fed high fat food during pregnancy (Vucetic et al, 2010). These offspring have elevated dopamine transporter (DAT) in the ventral tegmental area (VTA), NAc, and prefrontal cortex (PFC), and increased preproenkephalin and mu opioid receptors in the NAc and PFC (Vucetic et al., 2010). Interestingly, these alterations were associated with epigenetic modification (hypomethylation) of the promoter elements for all of the proteins affected.
Effects on the corticotropin-releasing factor (CRF) system by high fat/high sugar diets are also reminiscent of those imparted by drugs of abuse. CRF in the amygdala was increased following a 24 hour withdrawal from a high fat diet, while animals maintained on this diet had unaltered amygdala CRF (Teegarden and Bale, 2007). In preclinical models, this altered CRF signaling is thought to underlie negative reinforcement processes and increased “binge” intake of ethanol (Koob, 2010). As a result, CRF antagonists are being proposed for the treatment of alcoholism and drug addiction (Sarnyai et al, 2001; Koob et al, 2009; Lowery and Thiele, 2010). Based on these data, CRF antagonists may also be expected to help individuals remain abstinent from high fat/high sugar foods during a transition to a healthier diet.
Transcription factors are another class of molecule implicated in mediating enduring effects of drugs of abuse by directly affecting gene expression (McClung and Nestler, 2008). In support of the idea that food is capable of inducing neural plasticity, several transcription factors are also altered by diet. NAc phospho-CREB was reduced 24 hours following withdrawal from a high carbohydrate diet and both 24 hours and 1 week following withdrawal from a high fat diet, while the transcription factor delta FosB is increased during access to high fat diet (Teegarden and Bale, 2007) or sucrose (Wallace et al, 2008). In the NAc, decreased phospho-CREB is also seen during periods of withdrawal from amphetamine and morphine (McDaid et al, 2006a; McDaid et al, 2006b), and delta FosB is also increased following withdrawal from these drugs as well as cocaine, nicotine, ethanol, and phencyclidine (McClung et al, 2004; McDaid et al., 2006a; McDaid et al., 2006b). Similar to their proposed role in increasing drug seeking behavior, these neuroadaptations may also affect subsequent feeding behavior, as overexpression of delta FosB in the ventral striatum increases motivation to obtain food (Olausson et al, 2006) and sucrose (Wallace et al., 2008).
Synaptic plasticity in addiction-related circuitry has been linked with in vivo administration of numerous drugs of abuse. In the VTA, several classes of addictive, but not non-addictive psychoactive drugs induce synaptic plasticity (Saal et al, 2003; Stuber et al, 2008a; Wanat et al, 2009a). To date, there is very little data directly measuring the effects of food on synaptic plasticity in addiction-related neurocircuitry. Operant learning associated with food (chow or sucrose pellets) increased AMPA/NMDA ratios in the ventral tegmental area for up to seven days following training (Chen et al, 2008a). When cocaine was self-administered, the effect lasted up to three months, and this effect was not seen with passive administration of cocaine (Chen et al., 2008a). Miniature EPSP frequency in the VTA was also increased for up to three months following cocaine self-administration, and up to three weeks following sucrose (but not chow) self-administration, suggesting that glutamatergic signaling is strengthened pre- and post-synaptically (Chen et al., 2008a).
These data suggest that some measures of synaptic plasticity in the mesolimbic system (e.g. AMPA/NMDA ratios) may be associated with appetitive learning in general. This is supported by the fact that Pavlovian learning associated with food reward occluded VTA LTP during acquisition (day 3 of conditioning) (Stuber et al, 2008b). Although evidence of plasticity was observed on day 3, it was absent two days later, suggesting that self-administration distinctly leads to more enduring plasticity in these circuits (Stuber et al., 2008b). This appears to also be the case for plasticity associated with cocaine self-administration, as repeated non-contingent cocaine-induced plasticity in the VTA is also short-lived (Borgland et al, 2004; Chen et al., 2008a). The nature of these operant studies does not, however, discount the fact that extended access to palatable food may lead to protracted synaptic plasticity. During typical operant conditioning studies, animals are allowed much less access to food reward than during free-feeding or scheduled access. Future studies will need to be conducted to determine the effects of extended access to highly palatable food on synaptic plasticity.
3. Sexual Reward
Sex is a reward that, much like food, is critical for the survival of a species. Like food and several drugs of abuse, sexual behavior elevates mesolimbic DA (Meisel et al, 1993; Mermelstein and Becker, 1995). It is also a behavior that has been measured in terms of reinforcing value by operant (Beach and Jordan, 1956; Caggiula and Hoebel, 1966; Everitt et al, 1987; Crawford et al, 1993) and place conditioning methods (Paredes and Vazquez, 1999; Martinez and Paredes, 2001; Tzschentke, 2007). Human subjects in treatment for compulsive sexual behavior (categorized as “Sexual Disorder Not Otherwise Specified” in the DSM-IV) have many symptoms associated with drug addiction, including escalation, withdrawal, difficulty in stopping or reducing activity, and continued sexual behavior despite adverse consequences (Orford, 1978; Gold and Heffner, 1998; Garcia and Thibaut, 2010). Considering these adaptations in behavior, it is reasonable to imagine significant neuroadaptations occurring within mesocorticolimbic circuitry. As seen with repeated sugar exposure, repeated sexual encounters in male rats cross-sensitized with amphetamine in a locomotor assay (Pitchers et al, 2010a). Repeated sexual encounters also increase sucrose consumption and place preference for low dose amphetamine, suggesting cross-sensitization between sexual experience and drug reward (Wallace et al., 2008; Pitchers et al, 2010b). Also similar to the sensitizing effects of drugs of abuse (Segal and Mandell, 1974; Robinson and Becker, 1982; Robinson and Berridge, 2008), repeated sexual encounters sensitize the NAc DA response to a later sexual encounter (Kohlert and Meisel, 1999). Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA (Fiorino and Phillips, 1999).
As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009).
The MAP kinase signaling pathway is another plasticity-related pathway that is engaged during repeated sexual experience (Bradley et al, 2005). In sexually experienced females, a sexual encounter led to elevated pERK2 in the NAc (Meisel and Mullins, 2006). Increases in NAc pERK are induced by several drugs of abuse, but not by non-addictive psychoactive drugs, suggesting that NAc ERK activation may be associated with plasticity associated with addiction (Valjent et al, 2004). Further, a recent study found that pERK was induced by sexual activity in the same neurons of the NAc, basolateral amygdala, and anterior cingulate cortex that were previously activated by methamphetamine (Frohmader et al, 2010). This unique selectivity suggests that activation of this signaling cascade in NAc and other mesocorticolimbic regions may specifically lead to plasticity that promotes future appetitive behavior (Girault et al, 2007).
Neural structure in the mesocorticolimbic system is also altered following sexual experience. Pitchers and colleagues recently reported an increase in dendrites and dendritic spines within the NAc in rats during “withdrawal” from sexual experience (Pitchers et al., 2010a). This expands on other data demonstrating that sexual experience can alter dendritic morphology in a manner analogous to repeated drug exposure (Fiorino and Kolb, 2003; Robinson and Kolb, 2004; Meisel and Mullins, 2006).
4. Exercise Reward
Access to a running wheel for exercise serves as a reinforcer in laboratory rodents (Belke and Heyman, 1994; Belke and Dunlop, 1998; Lett et al, 2000). Like drugs of abuse and other natural rewards, exercise in rodents is associated with increased DA signaling in the NAc and striatum (Freed and Yamamoto, 1985; Hattori et al, 1994). Exercise also elevates brain and plasma levels of endogenous opioids in humans and rodents (Christie and Chesher, 1982; Janal et al, 1984; Schwarz and Kindermann, 1992; Asahina et al, 2003). One target of these opioids is the mu opiate receptor, a substrate of opiate drugs of abuse such as heroin and morphine. This overlap also appears to extend to behavioral responses to drugs of abuse. Unlike the natural rewards discussed thus far, most studies have found that exposure to exercise attenuates the effects of drugs of abuse. For example, self-administration of morphine, ethanol, and cocaine are all reduced following exercise (Cosgrove et al, 2002; Smith et al, 2008; Ehringer et al, 2009; Hosseini et al, 2009). Exercise experience attenuated CPP to MDMA and cocaine and also reduced the MDMA increase in NAc DA (Chen et al, 2008b; Thanos et al, 2010). Exercise prior to self-administration training was also able to reduce drug seeking and reinstatement, although in this study self-administration of cocaine was not affected (Zlebnik et al, 2010). In a similar study, cocaine seeking and cue reinstatement were reduced in rats that exercised during a period of drug abstinence (Lynch et al, 2010). In animals with a history of running wheel experience, withdrawal of wheel access leads to drug withdrawal-like symptoms including, increased anxiety and aggression, and susceptibility to naloxone-precipitated withdrawal (Hoffmann et al, 1987; Kanarek et al, 2009).
In addition to altered behavioral responses to drugs of abuse, there is neurochemical plasticity reflected by increased dynorphin in the striatum and NAc following running, a phenomenon also seen in human cocaine addicts and in animals following administration of cocaine or ethanol (Lindholm et al, 2000; Werme et al, 2000; Wee and Koob, 2010). Also reminiscent of drug associated neural plasticity, the transcription factor delta FosB is induced in the NAc of animals with wheel running experience (Werme et al, 2002). These changes may underlie the state of “withdrawal” that is observed following removal of running wheel access in animals with previous access (Hoffmann et al., 1987; Kanarek et al., 2009). Conversely, exercise during drug abstinence is also associated with a reduction in reinstatement-induced activation of ERK in the PFC (Lynch et al., 2010). This is an especially relevant finding considering the role of ERK in many aspects of addiction (Valjent et al., 2004; Lu et al, 2006; Girault et al., 2007) and the finding that ERK activation within the PFC is associated with incubation of drug craving (Koya et al, 2009). Striatal levels of the dopamine D2 receptor have also been reported to increase following exercise (MacRae et al, 1987; Foley and Fleshner, 2008), an effect that is opposite to that observed following psychostimulant self-administration in rodents, primates, and humans (Volkow et al., 1990; Nader et al, 2002; Conrad et al., 2010). It is possible that these adaptations may contribute to a “protective” effect of exercise in regards to drug abuse/addiction. Support for this idea comes from studies mentioned earlier in this section demonstrating reduced drug self-administration, seeking, and reinstatement in animals allowed to exercise. There is also support that exercise can “out-compete” drug self-administration, as wheel running reduces amphetamine intake when both reinforcers were concurrently available (Kanarek et al, 1995).
Exercise also has effects within the hippocampus, where it influences plasticity (reflected in elevated LTP and improved spatial learning) and increases neurogenesis and the expression of several plasticity-related genes (Kanarek et al., 1995; van Praag et al, 1999; Gomez-Pinilla et al, 2002; Molteni et al, 2002). Decreased hippocampal neurogenesis has been linked with depressive-like behaviors in preclinical studies (Duman et al, 1999; Sahay and Hen, 2007), and consistent with an ability to increase hippocampal neurogenesis, exercise has been demonstrated to have an antidepressant effect in a depressive line of rats (Bjornebekk et al, 2006), and to improve depressive symptoms in human patients (Ernst et al, 2006). Considering a recently reported link between suppression of hippocampal neurogenesis and increased cocaine intake and seeking behaviors in the rat (Noonan et al, 2010) along with previous evidence that exposure to stress (a treatment that reduces hippocampal neurogenesis), increases drug intake (Covington and Miczek, 2005), it is important to consider effects of exercise on hippocampal function in addition to those on mesolimbic function. Because exercise leads to plasticity in both depression-related circuitry (i.e. hippocampal) and drug-seeking related circuitry (i.e. the mesolimbic system), it is difficult to determine where the precise locus of the “anti drug seeking” effects of exercise exists.
Consistent with the effects of exercise on drug rewards, there is also evidence that running can decrease preference for natural reinforcers. Under conditions of limited food access, rats with constant access to running wheel will actually cease to eat to the point of death (Routtenberg and Kuznesof, 1967; Routtenberg, 1968). This extreme phenomenon is observed only when periods of food access occur with continued access to a running wheel, although it may suggest that exposure to exercise may reduce motivation in a general manner for both drug and non-drug reinforcers. A final consideration of the effects of exercise is that a running wheel housed within the animal cage may act as a form of environmental enrichment. While it is difficult to completely dissociate environmental enrichment from exercise (EE housed animals exercise more), dissociable effects of EE and exercise have been reported (van Praag et al., 1999; Olson et al, 2006).
5. Novelty/Sensory Stimulation/Environmental Enrichment
Novel stimuli, sensory stimulation, and enriched environments are all reinforcing to animals, including rodents (Van de Weerd et al, 1998; Besheer et al, 1999; Bevins and Bardo, 1999; Mellen and Sevenich MacPhee, 2001; Dommett et al, 2005; Cain et al, 2006; Olsen and Winder, 2009). Novel environments, sensory stimuli, and environmental enrichment (EE) have all been shown to activate the mesolimbic DA system (Chiodo et al, 1980; Horvitz et al, 1997; Rebec et al, 1997a; Rebec et al, 1997b; Wood and Rebec, 2004; Dommett et al., 2005; Segovia et al, 2010), suggesting overlap with addiction circuitry. In human populations, sensation and novelty seeking have been linked to susceptibility, intake, and severity of drug abuse (Cloninger, 1987; Kelly et al, 2006); for review, see (Zuckerman, 1986). In rodents, response to novelty has also been correlated with subsequent drug self-administration (Piazza et al, 1989; Cain et al, 2005; Meyer et al, 2010), suggesting that these two phenotypes covary. Based on these and neurochemical data, there is thought to be overlap in mesocorticolimbic circuitry that underlies response to novelty and drugs of abuse (Rebec et al., 1997a; Rebec et al., 1997b; Bardo and Dwoskin, 2004). Sensory stimuli (especially visual and auditory stimuli) have been studied for their reinforcing properties (Marx et al, 1955; Stewart, 1960; Cain et al., 2006; Liu et al, 2007; Olsen and Winder, 2010), and we have recently demonstrated an involvement of dopaminergic and glutamatergic signaling in mediating the reinforcing properties of varied sensory stimuli (Olsen and Winder, 2009; Olsen et al, 2010). Plasticity following discrete exposure to novelty or sensory stimuli within parameters that would not be aversive is limited, although there is extensive evidence for neural plasticity following strong activation or deprivation of sensory systems (Kaas, 1991; Rauschecker, 1999; Uhlrich et al, 2005; Smith et al, 2009). However, there is a wealth of data on neural plasticity associated with housing in an enriched environment (which includes aspects of other topics discussed, including novelty and exercise; for more in-depth reviews, see (Kolb and Whishaw, 1998; van Praag et al, 2000a; Nithianantharajah and Hannan, 2006)). Hebb’s renowned theory of learning was influenced by results he obtained demonstrating that rats housed in an enriched environment (his own house) performed better at learning tasks than littermates housed in the laboratory (Hebb, 1947). Subsequent studies have identified drastic changes in brain weight, angiogenesis, neurogenesis, gliogenesis, and dendritic structure in response to environmental enrichment (EE) (Bennett et al, 1969; Greenough and Chang, 1989; Kolb and Whishaw, 1998; van Praag et al, 2000b). More recent data from microarray studies have shown that EE housing induces expression of gene cascades involved with NMDA-dependent plasticity and neuroprotection (Rampon et al, 2000). The same group found that exposure to the EE environment for only 3 hours (i.e. exposure to numerous novel stimuli) had similar results, increasing gene expression in pathways associated with neuritogenesis and plasticity (Rampon et al., 2000).
Like exercise reward, as a general trend the plasticity induced by EE appears to reduce the sensitivity to drugs of abuse and may impart a “protective phenotype” against drug taking (Stairs and Bardo, 2009; Thiel et al, 2009; Solinas et al, 2010; Thiel et al, 2011). Compared to animals in impoverished conditions, EE produced a rightward shift in the dose-response curve of locomotor activation by morphine, as well as attenuated morphine- and amphetamine-induced locomotor sensitization (Bardo et al, 1995; Bardo et al, 1997). A similar trend was observed following psychostimulant treatment, where EE attenuated the locomotor activating and sensitization effects of nicotine and reduced cocaine self-administration and seeking behavior (although EE increased cocaine CPP) (Green et al, 2003; Green et al, 2010). Interestingly, EE did not lead to differences in NAc or striatal DA synthesis or mu opiate receptor binding in several mesocorticolimbic areas investigated (Bardo et al., 1997), although Segovia and colleagues did find an increase in basal and K+-stimulated NAc DA following EE (Segovia et al., 2010). In the PFC (but not NAc or striatum), EE rats were found to have reduced dopamine transport capacity (Zhu et al, 2005). This resulting increase in prefrontal DA signaling could impact mesolimbic activity, impulsivity, and drug self-administration (Deutch, 1992; Olsen and Duvauchelle, 2001, 2006; Everitt et al., 2008; Del Arco and Mora, 2009). More recent work has identified attenuated activity of CREB and reduced BDNF in the NAc following 30 days EE compared to impoverished rats (Green et al., 2010), although NAc BDNF levels were similar between EE and control rats following one year of housing (Segovia et al., 2010). EE also affects transcriptional activity induced by drugs of abuse. Induction of the immediate early gene zif268 in the NAc by cocaine is reduced, as is cocaine-induced expression of delta FosB in the striatum (although EE itself was found to elevate striatal delta FosB) (Solinas et al, 2009). This “protective” effect is not just seen in the field of addiction. The degree of plasticity induced by EE is so great that it is continuing to be studied in terms of protecting and improving recovery from several neurological diseases (van Praag et al., 2000a; Spires and Hannan, 2005; Nithianantharajah and Hannan, 2006; Laviola et al, 2008; Lonetti et al, 2010), and a recent report even found a hypothalamic-dependent increase in cancer remission when animals were housed in EE (Cao et al, 2010). As discussed in regards to exercise, conclusions regarding the effects of EE on drug self-administration should be made while considering the potential anti-depressive effects of enriched housing. Like exercise, EE has been demonstrated to increase hippocampal neurogenesis (van Praag et al., 2000b) and reduce the depressive-like effects of stress in rodents (Laviola et al., 2008).
In some people, there is a transition from “normal” to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). As research in non-drug addiction progresses, knowledge gained from the fields of drug addiction, motivation, and obsessive-compulsive disorder will contribute to the development of therapeutic strategies for non-drug addictions. There is emerging clinical evidence that pharmacotherapies used to treat drug addiction may be a successful approach to treating non-drug addictions. For example, naltrexone, nalmefine, N-acetyl-cysteine, and modafanil have all been reported to reduce craving in pathological gamblers (Kim et al, 2001; Grant et al, 2006b; Leung and Cottler, 2009). Opiate antagonists have also shown promise in small studies in the treatment of compulsive sexual behavior (Grant and Kim, 2001), and topirimate has shown success in reducing binge episodes and weight in obese patients with binge eating disorder (McElroy et al, 2007). The success of these treatments for non-drug addictions further suggests that there are common neural substrates between drug and non-drug addictions.
Animal models of motivated and compulsive behavior will also help provide insight into neural mechanisms underlying non-drug addictions (Potenza, 2009; Winstanley et al, 2010). Some types of non-drug addictions are more easily modeled in rodents than others. For example, paradigms using access to highly palatable foods have provided an excellent framework for the study of the transition to compulsive or excessive food intake. Rodent models using access to high fat, high sugar, or “cafeteria style” diet result in increased caloric intake and elevated weight gain, principal components of human obesity (Rothwell and Stock, 1979, 1984; Lin et al, 2000). These treatments can increase future motivation for food reward (Wojnicki et al, 2006) and lead to alterations in neural plasticity in the mesolimbic dopamine system (Hoebel et al, 2009). Food self-administration models have further found that food-associated cues and stressors can lead to relapse to food seeking (Ward et al., 2007; Grimm et al, 2008; Nair et al., 2009b), a phenomenon also reported for human dieters (Drewnowski, 1997; Berthoud, 2004). Thus, these types of models have high construct validity and may result in neuroadaptations that give us insight into human conditions such as compulsive food intake or relapse to excessive eating habits following a beneficial change in diet.
Another area of recent progress has been in the development of rodent models of gambling and risky choice (van den Bos et al, 2006; Rivalan et al, 2009; St Onge and Floresco, 2009; Zeeb et al., 2009; Jentsch et al, 2010). Studies have demonstrated that rats are capable of performing the Iowa gambling task (IGT) (Rivalan et al., 2009; Zeeb et al., 2009) and a slot machine task (Winstanley et al, 2011). One study found that rats that performed suboptimally on the IGT had higher reward sensitivity and higher risk taking (Rivalan et al., 2009), similar to traits that have been associated with pathological gambling and drug addiction in human patients (Cloninger, 1987; Zuckerman, 1991; Cunningham-Williams et al, 2005; Potenza, 2008). Using rodent models, studies are also focusing on neural mechanisms underlying the “drive to gamble” and the development of pathological gambling which may provide insight into development of pharmacotherapies for pathological gambling (Winstanley, 2011; Winstanley et al., 2011).
Mechanistic studies using sensory stimuli as a reinforcer have found overlap of the molecular mechanisms that modulate self-administration of sensory reinforcers and drugs of abuse (Olsen and Winder, 2009; Olsen et al., 2010). While research in this field is in its infancy, these and future experiments may give insight into potential therapeutic strategies for the treatment of compulsive internet use or video gaming.
While these and other advancements in behavioral models are beginning to give us potential insight into processes underlying non-drug addictions, there are several challenges and limitations when attempting to model such behavior. One limitation is that in most models, there is no significant consequence of maladaptive decision-making or excessive engagement in the behaviors. For example, rodent gambling tasks use smaller rewards or increased delay between rewards in response to poor decisions, but the animal doesn’t risk losing his home after a losing streak. Another limitation is that excessive engagement in behaviors such as food or drug self-administration in laboratory conditions may be a consequence of animals not having access to other non-drug rewards (Ahmed, 2005). This unique situation has been proposed to model risk-prone individuals in human populations (Ahmed, 2005), although it still represents a caveat for these types of studies.
Continued study of excessive, compulsive, or maladaptive performance in eating, gambling, and other non-drug behaviors will be key in advancing our understanding of non-drug addictions. Results from preclinical studies using these methods combined with research in human populations will promote “crossover” pharmacotherapies that could benefit both drug and non-drug addictions (Grant et al., 2006a; Potenza, 2009; Frascella et al., 2010).
6.1 Remaining Questions
One question that remains is whether the same populations of neurons are activated by drug and natural rewards. While there is ample evidence that there is overlap in the brain regions affected by natural rewards and drugs of abuse (Garavan et al, 2000; Karama et al, 2002; Childress et al, 2008), there is conflicting data regarding overlap in neural populations that are affected by natural rewards and drugs. Single unit recordings from rat and non-human primate ventral striatum indicate that different neural populations are engaged during self-administration of natural rewards (food, water, and sucrose) vs. cocaine or ethanol, although there was a high degree of overlap between the different natural rewards used in these studies (Bowman et al, 1996; Carelli et al, 2000; Carelli, 2002; Robinson and Carelli, 2008). There is also evidence that drugs of different classes engage distinct neural ensembles within the mesocorticolimbic system. Single unit recordings from the medial PFC and NAc of rats self-administering cocaine or heroin revealed that different populations of neurons were differentially engaged during both the anticipatory and post-infusion periods (Chang et al, 1998). The distinction between natural and drug reward may not be so absolute, however, as there is also evidence for the contrary. Following timed exposure to methamphetamine and sexual experience, there was significant coincidence of neurons activated by these two rewards in the NAc, anterior cingulate cortex, and basolateral amygdala (Frohmader et al., 2010). Thus, recruitment of neural populations by particular drugs of abuse may overlap with that of some natural rewards, but not others. Future studies using more comprehensive batteries of natural and drug rewards will be needed to address this issue.
Another question that arises is to what degree the study of natural reward processing can help us understand drug and non-drug addiction. Recent evidence suggests that exposure to some non-drug rewards can impart “protection” from drug rewards. For example, sugar and saccharin can reduce self-administration of cocaine and heroin (Carroll et al., 1989; Lenoir and Ahmed, 2008), and these natural reinforcers have been demonstrated to outcompete cocaine in choice self-administration in a large majority of rats (Lenoir et al., 2007; Cantin et al., 2010). In a retrospective analysis of animals across studies, Cantin et al. reported that only ~9% of rats prefer cocaine over saccharin. An interesting possibility is that this small proportion of animals represents a population that is susceptible to “addiction”. Studies using cocaine self-administration have attempted to identify “addicted” rats using criteria modified to model DSM-IV criteria for drug dependence (Deroche-Gamonet et al., 2004; Belin et al, 2009; Kasanetz et al, 2010). These studies have found that approximately ~17–20% of animals self-administering cocaine meet all three criteria, while estimates for rates of cocaine dependence in humans previously exposed to the drug range from ~5–15% (Anthony et al, 1994; O’Brien and Anthony, 2005). Thus, in the majority of animals sugar and saccharin appear to be more reinforcing than cocaine. A question of great interest is whether the minority of animals that find the drug reinforcer to be preferred represent a “vulnerable” population that is more relevant to the study of addiction. Thus, comparing individual animals’ preferences for drug versus natural rewards may yield insight into vulnerability factors associated with drug addiction.
A final question is whether the pursuit of natural rewards can help prevent or treat drug addiction. Environmental enrichment has been proposed as both a preventative and a treatment measure for drug addiction based on preclinical studies with several drugs of abuse (Bardo et al, 2001; Deehan et al, 2007; Solinas et al, 2008; Solinas et al., 2010). Studies of human inmates suggest that environmental enrichment through the use of “therapeutic communities” is in fact an effective treatment option both for reducing future crime and substance abuse (Inciardi et al, 2001; Butzin et al, 2005). These results are promising and suggest that environmental enrichment could potentially improve neuroadaptations associated with chronic drug use. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al, 2006; Prochaska et al, 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005).
7. Concluding Remarks
There are many parallels between non-drug addictions and drug addictions, including craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse (Marks, 1990; Lejoyeux et al., 2000; National Institute on Drug Abuse (NIDA) et al., 2002; Potenza, 2006). As I have reviewed, there is a glut of evidence that natural rewards are capable of inducing plasticity in addiction-related circuitry. This should not come as a surprise, as 1) drugs of abuse exert actions within the brain that are similar to, albeit more pronounced than natural rewards (Kelley and Berridge, 2002), and 2) learned associations between things such as food or sexual opportunities and the conditions which maximize availability is beneficial from a survival standpoint and is a natural function of the brain (Alcock, 2005). In some individuals, this plasticity may contribute to a state of compulsive engagement in behaviors that resembles drug addiction. Extensive data suggests that eating, shopping, gambling, playing video games, and spending time on the internet are behaviors that can develop into compulsive behaviors that are continued despite devastating consequences (Young, 1998; Tejeiro Salguero and Moran, 2002; Davis and Carter, 2009; Garcia and Thibaut, 2010; Lejoyeux and Weinstein, 2010). As with drug addiction, there is a transition period from moderate to compulsive use (Grant et al., 2006a), although it is difficult to draw a line between “normal” and pathological pursuit of reward. One potential approach to make this distinction is to test patients using DSM criteria for substance dependence. Using this approach, reports have been made that these DSM criteria can be met when applied to patients that compulsively engage in sexual activity (Goodman, 1992), gambling (Potenza, 2006), internet usage (Griffiths, 1998), and eating (Ifland et al, 2009). Taken with the fact that the DSM-5 is expected to include categories of moderate and severe within “addiction and related disorders” (American Psychiatric Association, 2010), it would perhaps serve addiction researchers and clinicians well to consider addiction as a spectrum disorder. In other fields, this type of nomenclature has helped to raise awareness that disorders such as autism and fetal alcoholism have numerous levels of severity. In the case of addiction (drug or non-drug), identification of symptoms even below the threshold of “moderate” may help identify at-risk individuals and allow for more effective interventions. Future studies will continue to reveal insights into how the pursuit of natural rewards can become compulsive in some individuals and how best to treat non-drug addictions.
Financial support was provided by NIH grant DA026994. I would like to thank Kelly Conrad, Ph.D. and Tiffany Wills, Ph.D. for constructive comments on previous versions of this manuscript.
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- (APA) APA DSM-5 Proposed Revisions Include New Category of Addiction and Related Disorders. 2010 [Press Release]. Retrieved from http://wwwdsm5org/newsroom/pages/pressreleasesaspx.
- Aghajanian GK. Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature. 1978;276:186–188. [PubMed]
- Ahmed SH. Imbalance between drug and non-drug reward availability: a major risk factor for addiction. Eur J Pharmacol. 2005;526:9–20. [PubMed]
- Ahmed SH, Koob GF. Transition from moderate to excessive drug intake: change in hedonic set point. Science. 1998;282:298–300. [PubMed]
- Aiken CB. Pramipexole in psychiatry: a systematic review of the literature. J Clin Psychiatry. 2007;68:1230–1236. [PubMed]
- Alburges ME, Narang N, Wamsley JK. Alterations in the dopaminergic receptor system after chronic administration of cocaine. Synapse. 1993;14:314–323. [PubMed]
- Alcock J. Animal Behavior: an evolutionary approach. Sinauer Associates; Sunderland, Mass: 2005.
- American Psychiatric Association A DSM-5 Proposed Revisions Include New Category of Addiction and Related Disorders. 2010 [Press Release]. Retrieved from http://wwwdsm5org/newsroom/pages/pressreleasesaspx.
- Antelman SM, Eichler AJ, Black CA, Kocan D. Interchangeability of stress and amphetamine in sensitization. Science. 1980;207:329–331. [PubMed]
- Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Experimental and Clinical Psychopharmacology. 1994;2:244–268.
- Asahina S, Asano K, Horikawa H, Hisamitsu T, Sato M. Enhancement of beta-endorphin levels in rat hypothalamus by exercise. Japanese Journal of Physical Fitness and Sports Medicine. 2003;5:159–166.
- Aston-Jones G, Harris GC. Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology. 2004;47(Suppl 1):167–179. [PubMed]
- Avena NM, Hoebel BG. Amphetamine-sensitized rats show sugar-induced hyperactivity (cross-sensitization) and sugar hyperphagia. Pharmacol Biochem Behav. 2003a;74:635–639. [PubMed]
- Avena NM, Hoebel BG. A diet promoting sugar dependency causes behavioral cross-sensitization to a low dose of amphetamine. Neuroscience. 2003b;122:17–20. [PubMed]
- Avena NM, Long KA, Hoebel BG. Sugar-dependent rats show enhanced responding for sugar after abstinence: evidence of a sugar deprivation effect. Physiol Behav. 2005;84:359–362. [PubMed]
- Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev. 2008;32:20–39. [PMC free article] [PubMed]
- Balleine BW, Dickinson A. Goal-directed instrumental action: contingency and incentive learning and their cortical substrates. Neuropharmacology. 1998;37:407–419. [PubMed]
- Bardo MT, Bowling SL, Rowlett JK, Manderscheid P, Buxton ST, Dwoskin LP. Environmental enrichment attenuates locomotor sensitization, but not in vitro dopamine release, induced by amphetamine. Pharmacol Biochem Behav. 1995;51:397–405. [PubMed]
- Bardo MT, Dwoskin LP. Biological connection between novelty- and drug-seeking motivational systems. Nebr Symp Motiv. 2004;50:127–158. [PubMed]
- Bardo MT, Klebaur JE, Valone JM, Deaton C. Environmental enrichment decreases intravenous self-administration of amphetamine in female and male rats. Psychopharmacology (Berl) 2001;155:278–284. [PubMed]
- Bardo MT, Robinet PM, Hammer RF., Jr. Effect of differential rearing environments on morphine-induced behaviors, opioid receptors and dopamine synthesis. Neuropharmacology. 1997;36:251–259. [PubMed]
- Beach FA, Jordan L. Effects of sexual reinforcement upon the performance of male rats in a straight runway. J Comp Physiol Psychol. 1956;49:105–110. [PubMed]
- Bechara A. Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective. Nat Neurosci. 2005;8:1458–1463. [PubMed]
- Belin D, Balado E, Piazza PV, Deroche-Gamonet V. Pattern of intake and drug craving predict the development of cocaine addiction-like behavior in rats. Biol Psychiatry. 2009;65:863–868. [PubMed]
- Belke TW, Dunlop L. Effects of high doses of naltrexone on running and responding for the opportunity to run in rats: A test of the opiate hypothesis. Psychol Rec. 1998;48:675–684.
- Belke TW, Heyman GM. A Matching Law Analysis of the Reinforcing Efficacy of Wheel Running in Rats. Anim Learn Behav. 1994;22:267–274.
- Bello NT, Lucas LR, Hajnal A. Repeated sucrose access influences dopamine D2 receptor density in the striatum. Neuroreport. 2002;13:1575–1578. [PMC free article] [PubMed]
- Bennett EL, Rosenzweig MR, Diamond MC. Rat brain: effects of environmental enrichment on wet and dry weights. Science. 1969;163:825–826. [PubMed]
- Berthoud HR. Mind versus metabolism in the control of food intake and energy balance. Physiol Behav. 2004;81:781–793. [PubMed]
- Besheer J, Jensen HC, Bevins RA. Dopamine antagonism in a novel-object recognition and a novel-object place conditioning preparation with rats. Behav Brain Res. 1999;103:35–44. [PubMed]
- Bevins RA, Bardo MT. Conditioned increase in place preference by access to novel objects: antagonism by MK-801. Behav Brain Res. 1999;99:53–60. [PubMed]
- Bevins RA, Besheer J. Novelty reward as a measure of anhedonia. Neurosci Biobehav Rev. 2005;29:707–714. [PubMed]
- Bjornebekk A, Mathe AA, Brene S. Running has differential effects on NPY, opiates, and cell proliferation in an animal model of depression and controls. Neuropsychopharmacology. 2006;31:256–264. [PubMed]
- Black DW. Compulsive buying disorder: a review of the evidence. Cns Spectrums. 2007;12:124–132. [PubMed]
- Borgland SL, Malenka RC, Bonci A. Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats. J Neurosci. 2004;24:7482–7490. [PubMed]
- Bowman EM, Aigner TG, Richmond BJ. Neural signals in the monkey ventral striatum related to motivation for juice and cocaine rewards. J Neurophysiol. 1996;75:1061–1073. [PubMed]
- Bradley KC, Boulware MB, Jiang H, Doerge RW, Meisel RL, Mermelstein PG. Changes in gene expression within the nucleus accumbens and striatum following sexual experience. Genes Brain Behav. 2005;4:31–44. [PubMed]
- Breiter HC, Aharon I, Kahneman D, Dale A, Shizgal P. Functional imaging of neural responses to expectancy and experience of monetary gains and losses. Neuron. 2001;30:619–639. [PubMed]
- Bruijnzeel AW. kappa-Opioid receptor signaling and brain reward function. Brain Res Rev. 2009;62:127–146. [PMC free article] [PubMed]
- Butler SL. Trading Drink and Drugs for Sweat and Blisters. The New York Times; New York: 2005.
- Butzin CA, Martin SS, Inciardi JA. Treatment during transition from prison to community and subsequent illicit drug use. J Subst Abuse Treat. 2005;28:351–358. [PubMed]
- Caggiula AR, Hoebel BG. “Copulation-reward site” in the posterior hypothalamus. Science. 1966;153:1284–1285. [PubMed]
- Cain ME, Green TA, Bardo MT. Environmental enrichment decreases responding for visual novelty. Behavioural Processes. 2006;73:360–366. [PMC free article] [PubMed]
- Cain ME, Saucier DA, Bardo MT. Novelty seeking and drug use: contribution of an animal model. Experimental & Clinical Psychopharmacology. 2005;13:367–375. [PubMed]
- Cantin L, Lenoir M, Augier E, Vanhille N, Dubreucq S, Serre F, et al. Cocaine is low on the value ladder of rats: possible evidence for resilience to addiction. PLoS One. 2010;5:e11592. [PMC free article] [PubMed]
- Cao L, Liu X, Lin EJ, Wang C, Choi EY, Riban V, et al. Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell. 2010;142:52–64. [PMC free article] [PubMed]
- Carelli RM. Nucleus accumbens cell firing during goal-directed behaviors for cocaine vs. ‘natural’ reinforcement. Physiol Behav. 2002;76:379–387. [PubMed]
- Carelli RM, Ijames SG, Crumling AJ. Evidence that separate neural circuits in the nucleus accumbens encode cocaine versus “natural” (water and food) reward. J Neurosci. 2000;20:4255–4266. [PubMed]
- Carlezon WA, Jr., Thomas MJ. Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacology. 2009;56(Suppl 1):122–132. [PMC free article] [PubMed]
- Carroll ME, Lac ST, Nygaard SL. A concurrently available nondrug reinforcer prevents the acquisition or decreases the maintenance of cocaine-reinforced behavior. Psychopharmacology (Berl) 1989;97:23–29. [PubMed]
- Cassens G, Actor C, Kling M, Schildkraut JJ. Amphetamine withdrawal: effects on threshold of intracranial reinforcement. Psychopharmacology (Berl) 1981;73:318–322. [PubMed]
- Chang JY, Janak PH, Woodward DJ. Comparison of mesocorticolimbic neuronal responses during cocaine and heroin self-administration in freely moving rats. J Neurosci. 1998;18:3098–3115. [PubMed]
- Chen BT, Bowers MS, Martin M, Hopf FW, Guillory AM, Carelli RM, et al. Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA. Neuron. 2008a;59:288–297. [PMC free article] [PubMed]
- Chen BT, Hopf FW, Bonci A. Synaptic plasticity in the mesolimbic system: therapeutic implications for substance abuse. Ann N Y Acad Sci. 2010;1187:129–139. [PMC free article] [PubMed]
- Chen HI, Kuo YM, Liao CH, Jen CJ, Huang AM, Cherng CG, et al. Long-term compulsive exercise reduces the rewarding efficacy of 3,4-methylenedioxymethamphetamine. Behav Brain Res. 2008b;187:185–189. [PubMed]
- Childress AR, Ehrman RN, Wang Z, Li Y, Sciortino N, Hakun J, et al. Prelude to passion: limbic activation by “unseen” drug and sexual cues. PLoS One. 2008;3:e1506. [PMC free article] [PubMed]
- Chiodo LA, Antelman SM, Caggiula AR, Lineberry CG. Sensory stimuli alter the discharge rate of dopamine (DA) neurons: evidence for two functional types of DA cells in the substantia nigra. Brain Res. 1980;189:544–549. [PubMed]
- Christie MJ, Chesher GB. Physical dependence on physiologically released endogenous opiates. Life Sci. 1982;30:1173–1177. [PubMed]
- Clark PJ, Kohman RA, Miller DS, Bhattacharya TK, Haferkamp EH, Rhodes JS. Adult hippocampal neurogenesis and c-Fos induction during escalation of voluntary wheel running in C57BL/6J mice. Behav Brain Res. 2010;213:246–252. [PMC free article] [PubMed]
- Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science. 1987;236:410–416. [PubMed]
- Colantuoni C, Rada P, McCarthy J, Patten C, Avena NM, Chadeayne A, et al. Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence. Obes Res. 2002;10:478–488. [PubMed]
- Colantuoni C, Schwenker J, McCarthy J, Rada P, Ladenheim B, Cadet JL, et al. Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain. Neuroreport. 2001;12:3549–3552. [PubMed]
- Conrad KL, Ford K, Marinelli M, Wolf ME. Dopamine receptor expression and distribution dynamically change in the rat nucleus accumbens after withdrawal from cocaine self-administration. Neuroscience. 2010;169:182–194. [PMC free article] [PubMed]
- Contet C, Filliol D, Matifas A, Kieffer BL. Morphine-induced analgesic tolerance, locomotor sensitization and physical dependence do not require modification of mu opioid receptor, cdk5 and adenylate cyclase activity. Neuropharmacology. 2008;54:475–486. [PubMed]
- Corsica JA, Pelchat ML. Food addiction: true or false? Curr Opin Gastroenterol. 2010;26:165–169. [PubMed]
- Cosgrove KP, Hunter RG, Carroll ME. Wheel-running attenuates intravenous cocaine self-administration in rats: sex differences. Pharmacol Biochem Behav. 2002;73:663–671. [PubMed]
- Cottone P, Sabino V, Steardo L, Zorrilla EP. Opioid-dependent anticipatory negative contrast and binge-like eating in rats with limited access to highly preferred food. Neuropsychopharmacology. 2008;33:524–535. [PubMed]
- Covington HE, 3rd, Miczek KA. Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges” Psychopharmacology (Berl) 2001;158:388–398. [PubMed]
- Covington HE, 3rd, Miczek KA. Intense cocaine self-administration after episodic social defeat stress, but not after aggressive behavior: dissociation from corticosterone activation. Psychopharmacology (Berl) 2005;183:331–340. [PubMed]
- Crawford LL, Holloway KS, Domjan M. The nature of sexual reinforcement. J Exp Anal Behav. 1993;60:55–66. [PMC free article] [PubMed]
- Crombag HS, Gorny G, Li Y, Kolb B, Robinson TE. Opposite effects of amphetamine self-administration experience on dendritic spines in the medial and orbital prefrontal cortex. Cereb Cortex. 2005;15:341–348. [PubMed]
- Cunningham-Williams RM, Grucza RA, Cottler LB, Womack SB, Books SJ, Przybeck TR, et al. Prevalence and predictors of pathological gambling: results from the St. Louis personality, health and lifestyle (SLPHL) study. J Psychiatr Res. 2005;39:377–390. [PMC free article] [PubMed]
- Daniel JZ, Cropley M, Fife-Schaw C. The effect of exercise in reducing desire to smoke and cigarette withdrawal symptoms is not caused by distraction. Addiction. 2006;101:1187–1192. [PubMed]
- Davis C, Carter JC. Compulsive overeating as an addiction disorder. A review of theory and evidence. Appetite. 2009;53:1–8. [PubMed]
- Davis JF, Tracy AL, Schurdak JD, Tschop MH, Lipton JW, Clegg DJ, et al. Exposure to elevated levels of dietary fat attenuates psychostimulant reward and mesolimbic dopamine turnover in the rat. Behav Neurosci. 2008;122:1257–1263. [PMC free article] [PubMed]
- Deadwyler SA. Electrophysiological correlates of abused drugs: relation to natural rewards. Ann N Y Acad Sci. 2010;1187:140–147. [PubMed]
- Deehan GA, Jr., Cain ME, Kiefer SW. Differential rearing conditions alter operant responding for ethanol in outbred rats. Alcohol Clin Exp Res. 2007;31:1692–1698. [PubMed]
- Del Arco A, Mora F. Neurotransmitters and prefrontal cortex-limbic system interactions: implications for plasticity and psychiatric disorders. J Neural Transm. 2009;116:941–952. [PubMed]
- Deroche-Gamonet V, Belin D, Piazza PV. Evidence for addiction-like behavior in the rat. Science. 2004;305:1014–1017. see comment. [PubMed]
- Deutch AY. The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia. J Neural Transm Suppl. 1992;36:61–89. [PubMed]
- Dommett E, Coizet V, Blaha CD, Martindale J, Lefebvre V, Walton N, et al. How visual stimuli activate dopaminergic neurons at short latency. Science. 2005;307:1476–1479. [PubMed]
- Drewnowski A. Taste preferences and food intake. Annu Rev Nutr. 1997;17:237–253. [PubMed]
- Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry. 1999;46:1181–1191. [PubMed]
- Ehringer MA, Hoft NR, Zunhammer M. Reduced alcohol consumption in mice with access to a running wheel. Alcohol. 2009;43:443–452. [PubMed]
- Epping-Jordan MP, Watkins SS, Koob GF, Markou A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature. 1998;393:76–79. [PubMed]
- Ernst C, Olson AK, Pinel JP, Lam RW, Christie BR. Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis? J Psychiatry Neurosci. 2006;31:84–92. [PMC free article] [PubMed]
- Ettenberg A, Camp CH. Haloperidol induces a partial reinforcement extinction effect in rats: implications for a dopamine involvement in food reward. Pharmacol Biochem Behav. 1986;25:813–821. [PubMed]
- Evans AH, Pavese N, Lawrence AD, Tai YF, Appel S, Doder M, et al. Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Ann Neurol. 2006;59:852–858. [PubMed]
- Everitt BJ, Belin D, Economidou D, Pelloux Y, Dalley JW, Robbins TW. Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Philos Trans R Soc Lond B Biol Sci. 2008;363:3125–3135. [PMC free article] [PubMed]
- Everitt BJ, Dickinson A, Robbins TW. The neuropsychological basis of addictive behaviour. Brain Res Brain Res Rev. 2001;36:129–138. [PubMed]
- Everitt BJ, Fray P, Kostarczyk E, Taylor S, Stacey P. Studies of instrumental behavior with sexual reinforcement in male rats (Rattus norvegicus): I. Control by brief visual stimuli paired with a receptive female. J Comp Psychol. 1987;101:395–406. [PubMed]
- Fiorino DF, Kolb BS. Sexual experience leads to long-lasting morphological changes in male rat prefrontal cortex, parietal cortex, and nucleus accumbens neurons. Society for Neuroscience; New Orleans, LA: 2003. 2003 Abstract Viewer and Itinerary Planner Washington, DC.
- Fiorino DF, Phillips AG. Facilitation of sexual behavior and enhanced dopamine efflux in the nucleus accumbens of male rats after D-amphetamine-induced behavioral sensitization. J Neurosci. 1999;19:456–463. [PubMed]
- Foley TE, Fleshner M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. Neuromolecular Med. 2008;10:67–80. [PubMed]
- Frascella J, Potenza MN, Brown LL, Childress AR. Shared brain vulnerabilities open the way for nonsubstance addictions: carving addiction at a new joint? Ann N Y Acad Sci. 2010;1187:294–315. [PMC free article] [PubMed]
- Freed CR, Yamamoto BK. Regional brain dopamine metabolism: a marker for the speed, direction, and posture of moving animals. Science. 1985;229:62–65. [PubMed]
- Frohmader KS, Wiskerke J, Wise RA, Lehman MN, Coolen LM. Methamphetamine acts on subpopulations of neurons regulating sexual behavior in male rats. Neuroscience. 2010;166:771–784. [PMC free article] [PubMed]
- Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L, Ross TJ, et al. Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry. 2000;157:1789–1798. [PubMed]
- Garcia FD, Thibaut F. Sexual Addictions. Am J Drug Alcohol Abuse. 2010 [PubMed]
- Girault JA, Valjent E, Caboche J, Herve D. ERK2: a logical AND gate critical for drug-induced plasticity? Current Opinion in Pharmacology. 2007;7:77–85. [PubMed]
- Gold SN, Heffner CL. Sexual addiction: many conceptions, minimal data. Clin Psychol Rev. 1998;18:367–381. [PubMed]
- Gomez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol. 2002;88:2187–2195. [PubMed]
- Goodman A. Sexual addiction: designation and treatment. J Sex Marital Ther. 1992;18:303–314. [PubMed]
- Gosnell BA. Sucrose intake enhances behavioral sensitization produced by cocaine. Brain Res. 2005;1031:194–201. [PubMed]
- Gosnell BA, Levine AS. Reward systems and food intake: role of opioids. Int J Obes (Lond) 2009;33(Suppl 2):S54–58. [PubMed]
- Grant JE, Brewer JA, Potenza MN. The neurobiology of substance and behavioral addictions. Cns Spectrums. 2006a;11:924–930. [PubMed]
- Grant JE, Kim SW. A case of kleptomania and compulsive sexual behavior treated with naltrexone. Annals of Clinical Psychiatry. 2001;13:229–231. [PubMed]
- Grant JE, Potenza MN, Hollander E, Cunningham-Williams R, Nurminen T, Smits G, et al. Multicenter investigation of the opioid antagonist nalmefene in the treatment of pathological gambling. American Journal of Psychiatry. 2006b;163:303–312. see comment. [PubMed]
- Grant JE, Potenza MN, Weinstein A, Gorelick DA. Introduction to behavioral addictions. Am J Drug Alcohol Abuse. 2010;36:233–241. [PMC free article] [PubMed]
- Graybiel AM. Habits, rituals, and the evaluative brain. Annu Rev Neurosci. 2008;31:359–387. [PubMed]
- Green TA, Alibhai IN, Roybal CN, Winstanley CA, Theobald DE, Birnbaum SG, et al. Environmental enrichment produces a behavioral phenotype mediated by low cyclic adenosine monophosphate response element binding (CREB) activity in the nucleus accumbens. Biol Psychiatry. 2010;67:28–35. [PMC free article] [PubMed]
- Green TA, Cain ME, Thompson M, Bardo MT. Environmental enrichment decreases nicotine-induced hyperactivity in rats. Psychopharmacology (Berl) 2003;170:235–241. [PubMed]
- Greenough WT, Chang FF. Plasticity of synapse structure and pattern in the cerebral cortex. In: Peters A, Jones EG, editors. Cerebral Cortex. vol. 7. Plenum; New York: 1989. pp. 391–440.
- Griffiths M. Internet addiction: Does it really exist? In: Gackenbach J, editor. Psychology and the Internet. Academic Press; San Diego, CA: 1998. pp. 61–75.
- Grimm JW, Fyall AM, Osincup DP. Incubation of sucrose craving: effects of reduced training and sucrose pre-loading. Physiol Behav. 2005;84:73–79. [PMC free article] [PubMed]
- Grimm JW, Hope BT, Wise RA, Shaham Y. Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature. 2001;412:141–142. [PMC free article] [PubMed]
- Grimm JW, Osincup D, Wells B, Manaois M, Fyall A, Buse C, et al. Environmental enrichment attenuates cue-induced reinstatement of sucrose seeking in rats. Behav Pharmacol. 2008;19:777–785. [PMC free article] [PubMed]
- Grueter BA, Gosnell HB, Olsen CM, Schramm-Sapyta NL, Nekrasova T, Landreth GE, et al. Extracellular-signal regulated kinase 1-dependent metabotropic glutamate receptor 5-induced long-term depression in the bed nucleus of the stria terminalis is disrupted by cocaine administration. J Neurosci. 2006;26:3210–3219. [PubMed]
- Haber SN, Fudge JL, McFarland NR. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci. 2000;20:2369–2382. [PubMed]
- Hammer RP., Jr. Cocaine alters opiate receptor binding in critical brain reward regions. Synapse. 1989;3:55–60. [PubMed]
- Hattori S, Naoi M, Nishino H. Striatal dopamine turnover during treadmill running in the rat: relation to the speed of running. Brain Res Bull. 1994;35:41–49. [PubMed]
- He S, Grasing K. Chronic opiate treatment enhances both cocaine-reinforced and cocaine-seeking behaviors following opiate withdrawal. Drug Alcohol Depend. 2004;75:215–221. [PubMed]
- Hebb DO. The effects of early experience on problem solving at maturity. Am Psychol. 1947;2:306–307.
- Hedges VL, Chakravarty S, Nestler EJ, Meisel RL. Delta FosB overexpression in the nucleus accumbens enhances sexual reward in female Syrian hamsters. Genes Brain Behav. 2009;8:442–449. [PMC free article] [PubMed]
- Herman JP, Stinus L, Le Moal M. Repeated stress increases locomotor response to amphetamine. Psychopharmacology (Berl) 1984;84:431–435. [PubMed]
- Hoebel BG, Avena NM, Bocarsly ME, Rada P. Natural Addiction: A Behavioral and Circuit Model Based on Sugar Addiction in Rats. Journal of Addiction Medicine. 2009;3:33–41. [PubMed]
- Hoebel BG, Hernandez L, Schwartz DH, Mark GP, Hunter GA. Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior: theoretical and clinical implications. Annals of the New York Academy of Sciences; New York: 1989.
- Hoeft F, Watson CL, Kesler SR, Bettinger KE, Reiss AL. Gender differences in the mesocorticolimbic system during computer game-play. J Psychiatr Res. 2008;42:253–258. [PubMed]
- Hoffmann P, Thoren P, Ely D. Effect of voluntary exercise on open-field behavior and on aggression in the spontaneously hypertensive rat (SHR) Behav Neural Biol. 1987;47:346–355. [PubMed]
- Holden C. ‘Behavioral’ addictions: do they exist? Science. 2001;294:980–982. [PubMed]
- Horvitz JC, Stewart T, Jacobs BL. Burst activity of ventral tegmental dopamine neurons is elicited by sensory stimuli in the awake cat. Brain Res. 1997;759:251–258. [PubMed]
- Hosseini M, Alaei HA, Naderi A, Sharifi MR, Zahed R. Treadmill exercise reduces self-administration of morphine in male rats. Pathophysiology. 2009;16:3–7. [PubMed]
- Hudson JI, Hiripi E, Pope HG, Jr., Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2007;61:348–358. [PMC free article] [PubMed]
- Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annual Review of Neuroscience. 2006;29:565–598. [PubMed]
- Ifland JR, Preuss HG, Marcus MT, Rourke KM, Taylor WC, Burau K, et al. Refined food addiction: a classic substance use disorder. Med Hypotheses. 2009;72:518–526. [PubMed]
- Inciardi JA, Martin SS, Surratt HS. Therapeutic communities in prisons and work release: Effective modalities for drug-involved offenders. In: Rawlings B, Yates R, editors. Therapeutic communities for the treatment of drug users. Jessica Kingsley; London: 2001. pp. 241–256.
- James W. Principles of Psychology. H. Holt and Company; New York: 1890.
- Janal MN, Colt EW, Clark WC, Glusman M. Pain sensitivity, mood and plasma endocrine levels in man following long-distance running: effects of naloxone. Pain. 1984;19:13–25. [PubMed]
- Jentsch JD, Woods JA, Groman SM, Seu E. Behavioral characteristics and neural mechanisms mediating performance in a rodent version of the Balloon Analog Risk Task. Neuropsychopharmacology. 2010;35:1797–1806. [PMC free article] [PubMed]
- Johnson PM, Kenny PJ. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci. 2010;13:635–641. [PMC free article] [PubMed]
- Kaas JH. Plasticity of sensory and motor maps in adult mammals. Annu Rev Neurosci. 1991;14:137–167. [PubMed]
- Kalivas PW, Lalumiere RT, Knackstedt L, Shen H. Glutamate transmission in addiction. Neuropharmacology. 2009;56(Suppl 1):169–173. [PMC free article] [PubMed]
- Kalivas PW, O’Brien C. Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology. 2008;33:166–180. [PubMed]
- Kalivas PW, Richardson-Carlson R, Van Orden G. Cross-sensitization between foot shock stress and enkephalin-induced motor activity. Biol Psychiatry. 1986;21:939–950. [PubMed]
- Kalivas PW, Stewart J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev. 1991;16:223–244. [PubMed]
- Kanarek RB, D’Anci KE, Jurdak N, Mathes WF. Running and addiction: precipitated withdrawal in a rat model of activity-based anorexia. Behav Neurosci. 2009;123:905–912. [PMC free article] [PubMed]
- Kanarek RB, Marks-Kaufman R, D’Anci KE, Przypek J. Exercise attenuates oral intake of amphetamine in rats. Pharmacol Biochem Behav. 1995;51:725–729. [PubMed]
- Kandel E, Schwartz J, Jessell T. Principles of Neural Science. McGraw-Hill Medical; New York: 2000.
- Karama S, Lecours AR, Leroux JM, Bourgouin P, Beaudoin G, Joubert S, et al. Areas of brain activation in males and females during viewing of erotic film excerpts. Hum Brain Mapp. 2002;16:1–13. [PubMed]
- Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M, Manzoni O, et al. Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science. 2010;328:1709–1712. [PubMed]
- Kauer JA, Malenka RC. Synaptic plasticity and addiction. Nat Rev Neurosci. 2007;8:844–858. [PubMed]
- Kelley AE. Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci Biobehav Rev. 2004;27:765–776. [PubMed]
- Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci. 2002;22:3306–3311. [PubMed]
- Kelley AE, Will MJ, Steininger TL, Zhang M, Haber SN. Restricted daily consumption of a highly palatable food (chocolate Ensure(R)) alters striatal enkephalin gene expression. Eur J Neurosci. 2003;18:2592–2598. [PubMed]
- Kelly TH, Robbins G, Martin CA, Fillmore MT, Lane SD, Harrington NG, et al. Individual differences in drug abuse vulnerability: d-amphetamine and sensation-seeking status. Psychopharmacology (Berl) 2006;189:17–25. [PMC free article] [PubMed]
- Kenny PJ. Brain reward systems and compulsive drug use. Trends Pharmacol Sci. 2007;28:135–141. [PubMed]
- Kim SW, Grant JE, Adson DE, Shin YC. Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling. Biological Psychiatry. 2001;49:914–921. [PubMed]
- Knutson B, Rick S, Wimmer GE, Prelec D, Loewenstein G. Neural predictors of purchases. Neuron. 2007;53:147–156. see comment. [PMC free article] [PubMed]
- Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, et al. Evidence for striatal dopamine release during a video game. Nature. 1998;393:266–268. [PubMed]
- Kohlert JG, Meisel RL. Sexual experience sensitizes mating-related nucleus accumbens dopamine responses of female Syrian hamsters. Behav Brain Res. 1999;99:45–52. [PubMed]
- Kolb B, Whishaw IQ. Brain plasticity and behavior. Annu Rev Psychol. 1998;49:43–64. [PubMed]
- Komisaruk BR, Whipple B, Crawford A, Liu WC, Kalnin A, Mosier K. Brain activation during vaginocervical self-stimulation and orgasm in women with complete spinal cord injury: fMRI evidence of mediation by the vagus nerves. Brain Research. 2004;1024:77–88. [PubMed]
- Koob G, Kreek MJ. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry. 2007;164:1149–1159. [PMC free article] [PubMed]
- Koob GF. The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res. 2010;1314:3–14. [PMC free article] [PubMed]
- Koob GF, Kenneth Lloyd G, Mason BJ. Development of pharmacotherapies for drug addiction: a Rosetta stone approach. Nat Rev Drug Discov. 2009;8:500–515. [PMC free article] [PubMed]
- Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology. 2001;24:97–129. [PubMed]
- Koob GF, Le Moal M. Review. Neurobiological mechanisms for opponent motivational processes in addiction. Philos Trans R Soc Lond B Biol Sci. 2008;363:3113–3123. [PMC free article] [PubMed]
- Koob GF, Stinus L, Le Moal M, Bloom FE. Opponent process theory of motivation: neurobiological evidence from studies of opiate dependence. Neurosci Biobehav Rev. 1989;13:135–140. [PubMed]
- Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35:217–238. [PMC free article] [PubMed]
- Koya E, Uejima JL, Wihbey KA, Bossert JM, Hope BT, Shaham Y. Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology. 2009;56(Suppl 1):177–185. [PMC free article] [PubMed]
- Lader M. Antiparkinsonian medication and pathological gambling. CNS Drugs. 2008;22:407–416. [PubMed]
- Laviola G, Hannan AJ, Macri S, Solinas M, Jaber M. Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. Neurobiol Dis. 2008;31:159–168. [PubMed]
- Le Magnen J. A role for opiates in food reward and food addiction. In: Capaldi ED, Powley TL, editors. Taste, Experience, and Feeding. American Psychological Association; Washington, DC: 1990. pp. 241–254.
- Lejoyeux M, Mc Loughlin M, Adinverted-?es J. Epidemiology of behavioral dependence: literature review and results of original studies. European Psychiatry: the Journal of the Association of European Psychiatrists. 2000;15:129–134. [PubMed]
- Lejoyeux M, Weinstein A. Compulsive buying. Am J Drug Alcohol Abuse. 2010;36:248–253. [PubMed]
- Lenoir M, Ahmed SH. Supply of a nondrug substitute reduces escalated heroin consumption. Neuropsychopharmacology. 2008;33:2272–2282. [PubMed]
- Lenoir M, Serre F, Cantin L, Ahmed SH. Intense sweetness surpasses cocaine reward. PLoS ONE. 2007;2:e698. [PMC free article] [PubMed]
- Leri F, Flores J, Rajabi H, Stewart J. Effects of cocaine in rats exposed to heroin. Neuropsychopharmacology. 2003;28:2102–2116. [PubMed]
- Lett BT. Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology (Berl) 1989;98:357–362. [PubMed]
- Lett BT, Grant VL, Byrne MJ, Koh MT. Pairings of a distinctive chamber with the aftereffect of wheel running produce conditioned place preference. Appetite. 2000;34:87–94. [PubMed]
- Leung KS, Cottler LB. Treatment of pathological gambling. Curr Opin Psychiatry. 2009;22:69–74. [PubMed]
- Lin S, Thomas TC, Storlien LH, Huang XF. Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes Relat Metab Disord. 2000;24:639–646. [PubMed]
- Lindholm S, Ploj K, Franck J, Nylander I. Repeated ethanol administration induces short- and long-term changes in enkephalin and dynorphin tissue concentrations in rat brain. Alcohol. 2000;22:165–171. [PubMed]
- Liu X, Palmatier MI, Caggiula AR, Donny EC, Sved AF. Reinforcement enhancing effect of nicotine and its attenuation by nicotinic antagonists in rats. Psychopharmacology (Berl) 2007;194:463–473. [PMC free article] [PubMed]
- Lonetti G, Angelucci A, Morando L, Boggio EM, Giustetto M, Pizzorusso T. Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice. Biol Psychiatry. 2010;67:657–665. [PubMed]
- Lowery EG, Thiele TE. Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism. CNS Neurol Disord Drug Targets. 2010;9:77–86. [PMC free article] [PubMed]
- Lu L, Grimm JW, Hope BT, Shaham Y. Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology. 2004;47(Suppl 1):214–226. [PubMed]
- Lu L, Koya E, Zhai H, Hope BT, Shaham Y. Role of ERK in cocaine addiction. Trends Neurosci. 2006;29:695–703. [PubMed]
- Luscher C, Bellone C. Cocaine-evoked synaptic plasticity: a key to addiction? Nat Neurosci. 2008;11:737–738. [PubMed]
- Lynch WJ, Piehl KB, Acosta G, Peterson AB, Hemby SE. Aerobic Exercise Attenuates Reinstatement of Cocaine-Seeking Behavior and Associated Neuroadaptations in the Prefrontal Cortex. Biol Psychiatry. 2010 [PMC free article] [PubMed]
- MacRae PG, Spirduso WW, Walters TJ, Farrar RP, Wilcox RE. Endurance training effects on striatal D2 dopamine receptor binding and striatal dopamine metabolites in presenescent older rats. Psychopharmacology (Berl) 1987;92:236–240. [PubMed]
- Maj M, Turchan J, Smialowska M, Przewlocka B. Morphine and cocaine influence on CRF biosynthesis in the rat central nucleus of amygdala. Neuropeptides. 2003;37:105–110. [PubMed]
- Majewska MD. Cocaine addiction as a neurological disorder: implications for treatment. NIDA Res Monogr. 1996;163:1–26. [PubMed]
- Mameli M, Bellone C, Brown MT, Luscher C. Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area. Nat Neurosci. 2011 [PubMed]
- Markou A, Koob GF. Postcocaine anhedonia. An animal model of cocaine withdrawal. Neuropsychopharmacology. 1991;4:17–26. [PubMed]
- Marks I. Behavioural (non-chemical) addictions.[see comment] British Journal of Addiction. 1990;85:1389–1394. [PubMed]
- Martinez I, Paredes RG. Only self-paced mating is rewarding in rats of both sexes. Horm Behav. 2001;40:510–517. [PubMed]
- Marx MH, Henderson RL, Roberts CL. Positive reinforcement of the bar-pressing response by a light stimulus following dark operant pretests with no after effect. J Comp Physiol Psychol. 1955;48:73–76. [PubMed]
- McBride WJ, Li TK. Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. Crit Rev Neurobiol. 1998;12:339–369. [PubMed]
- McClung CA, Nestler EJ. Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology. 2008;33:3–17. [PubMed]
- McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, Nestler EJ. DeltaFosB: a molecular switch for long-term adaptation in the brain. Brain Res Mol Brain Res. 2004;132:146–154. [PubMed]
- McDaid J, Dallimore JE, Mackie AR, Napier TC. Changes in accumbal and pallidal pCREB and deltaFosB in morphine-sensitized rats: correlations with receptor-evoked electrophysiological measures in the ventral pallidum. Neuropsychopharmacology. 2006a;31:1212–1226. [PMC free article] [PubMed]
- McDaid J, Graham MP, Napier TC. Methamphetamine-induced sensitization differentially alters pCREB and DeltaFosB throughout the limbic circuit of the mammalian brain. Mol Pharmacol. 2006b;70:2064–2074. [PubMed]
- McElroy SL, Hudson JI, Capece JA, Beyers K, Fisher AC, Rosenthal NR. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61:1039–1048. [PubMed]
- Meisel RL, Camp DM, Robinson TE. A microdialysis study of ventral striatal dopamine during sexual behavior in female Syrian hamsters. Behav Brain Res. 1993;55:151–157. [PubMed]
- Meisel RL, Mullins AJ. Sexual experience in female rodents: cellular mechanisms and functional consequences. Brain Res. 2006;1126:56–65. [PMC free article] [PubMed]
- Mellen J, Sevenich MacPhee M. Philosophy of environmental enrichment: Past, present, and future. Zoo Biology. 2001;20:211–226.
- Mermelstein PG, Becker JB. Increased extracellular dopamine in the nucleus accumbens and striatum of the female rat during paced copulatory behavior. Behav Neurosci. 1995;109:354–365. [PubMed]
- Meyer AC, Rahman S, Charnigo RJ, Dwoskin LP, Crabbe JC, Bardo MT. Genetics of novelty seeking, amphetamine self-administration and reinstatement using inbred rats. Genes Brain Behav. 2010 [PMC free article] [PubMed]
- Molteni R, Ying Z, Gomez-Pinilla F. Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray. Eur J Neurosci. 2002;16:1107–1116. [PubMed]
- Nader MA, Daunais JB, Moore T, Nader SH, Moore RJ, Smith HR, et al. Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology. 2002;27:35–46. [PubMed]
- Nair SG, Adams-Deutsch T, Epstein DH, Shaham Y. The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking. Prog Neurobiol. 2009a;89:18–45. [PMC free article] [PubMed]
- Nair SG, Adams-Deutsch T, Epstein DH, Shaham Y. The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking. Prog Neurobiol. 2009b [PMC free article] [PubMed]
- National Institute on Drug Abuse (NIDA) National Institute of Mental Health (NIMH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Reward and decision making: opportunities and future directions. Neuron. 2002;36:189–192. [PubMed]
- Nestler EJ, Kelz MB, Chen J. DeltaFosB: a molecular mediator of long-term neural and behavioral plasticity. Brain Res. 1999;835:10–17. [PubMed]
- Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006;7:697–709. [PubMed]
- Noonan MA, Bulin SE, Fuller DC, Eisch AJ. Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction. J Neurosci. 2010;30:304–315. [PMC free article] [PubMed]
- O’Brien CP. Anticraving medications for relapse prevention: a possible new class of psychoactive medications. Am J Psychiatry. 2005;162:1423–1431. [PubMed]
- O’Brien CP. Commentary on Tao et al. (2010): Internet addiction and DSM-V. Addiction. 2010;105:565.
- O’Brien MS, Anthony JC. Risk of Becoming Cocaine Dependent: Epidemiological Estimates for the United States, 2000–2001. Neuropsychopharmacology. 2005 [PubMed]
- O’Donnell JM, Miczek KA. No tolerance to antiaggressive effect of d-amphetamine in mice. Psychopharmacology (Berl) 1980;68:191–196. [PubMed]
- Olausson P, Jentsch JD, Tronson N, Neve RL, Nestler EJ, Taylor JR. DeltaFosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation. J Neurosci. 2006;26:9196–9204. [PubMed]
- Olsen CM, Childs DS, Stanwood GD, Winder DG. Operant sensation seeking requires metabotropic glutamate receptor 5 (mGluR5) PLoS One. 2010;5:e15085. [PMC free article] [PubMed]
- Olsen CM, Duvauchelle CL. Intra-prefrontal cortex injections of SCH 23390 influence nucleus accumbens dopamine levels 24 h post-infusion. Brain Res. 2001;922:80–86. [PubMed]
- Olsen CM, Duvauchelle CL. Prefrontal cortex D1 modulation of the reinforcing properties of cocaine. Brain Research. 2006;1075:229–235. [PubMed]
- Olsen CM, Winder DG. Operant sensation seeking engages similar neural substrates to operant drug seeking in C57 mice. Neuropsychopharmacology. 2009;34:1685–1694. [PMC free article] [PubMed]
- Olsen CM, Winder DG. Operant sensation seeking in the mouse. J Vis Exp. 2010 [PMC free article] [PubMed]
- Olson AK, Eadie BD, Ernst C, Christie BR. Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus. 2006;16:250–260. [PubMed]
- Orford J. Hypersexuality: implications for a theory of dependence. Br J Addict Alcohol Other Drugs. 1978;73:299–210. [PubMed]
- Ostlund SB, Balleine BW. On habits and addiction: An associative analysis of compulsive drug seeking. Drug Discov Today Dis Models. 2008;5:235–245. [PMC free article] [PubMed]
- Packard MG, Knowlton BJ. Learning and memory functions of the Basal Ganglia. Annu Rev Neurosci. 2002;25:563–593. [PubMed]
- Paredes RG, Vazquez B. What do female rats like about sex? Paced mating. Behav Brain Res. 1999;105:117–127. [PubMed]
- Petry NM. Should the scope of addictive behaviors be broadened to include pathological gambling? Addiction. 2006;101(Suppl 1):152–160. [PubMed]
- Piazza PV, Deminiere JM, Le Moal M, Simon H. Factors that predict individual vulnerability to amphetamine self-administration. Science. 1989;245:1511–1513. [PubMed]
- Pierce RC, Vanderschuren LJ. Kicking the habit: The neural basis of ingrained behaviors in cocaine addiction. Neurosci Biobehav Rev. 2010 [PMC free article] [PubMed]
- Pitchers KK, Balfour ME, Lehman MN, Richtand NM, Yu L, Coolen LM. Neuroplasticity in the mesolimbic system induced by natural reward and subsequent reward abstinence. Biol Psychiatry. 2010a;67:872–879. [PMC free article] [PubMed]
- Pitchers KK, Frohmader KS, Vialou V, Mouzon E, Nestler EJ, Lehman MN, et al. DeltaFosB in the nucleus accumbens is critical for reinforcing effects of sexual reward. Genes Brain Behav. 2010b [PMC free article] [PubMed]
- Porrino LJ, Daunais JB, Smith HR, Nader MA. The expanding effects of cocaine: studies in a nonhuman primate model of cocaine self-administration. Neurosci Biobehav Rev. 2004a;27:813–820. [PubMed]
- Porrino LJ, Lyons D, Smith HR, Daunais JB, Nader MA. Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains. J Neurosci. 2004b;24:3554–3562. [PubMed]
- Potenza MN. Should addictive disorders include non-substance-related conditions? Addiction. 2006;101(Suppl 1):142–151. [PubMed]
- Potenza MN. Review. The neurobiology of pathological gambling and drug addiction: an overview and new findings. Philos Trans R Soc Lond B Biol Sci. 2008;363:3181–3189. [PMC free article] [PubMed]
- Potenza MN. The importance of animal models of decision making, gambling, and related behaviors: implications for translational research in addiction. Neuropsychopharmacology. 2009;34:2623–2624. [PMC free article] [PubMed]
- Prochaska JJ, Hall SM, Humfleet G, Munoz RF, Reus V, Gorecki J, et al. Physical activity as a strategy for maintaining tobacco abstinence: a randomized trial. Prev Med. 2008;47:215–220. [PMC free article] [PubMed]
- Rampon C, Tang YP, Goodhouse J, Shimizu E, Kyin M, Tsien JZ. Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat Neurosci. 2000;3:238–244. [PubMed]
- Rauschecker JP. Auditory cortical plasticity: a comparison with other sensory systems. Trends Neurosci. 1999;22:74–80. [PubMed]
- Rebec GV, Christensen JR, Guerra C, Bardo MT. Regional and temporal differences in real-time dopamine efflux in the nucleus accumbens during free-choice novelty. Brain Research. 1997a;776:61–67. [PubMed]
- Rebec GV, Grabner CP, Johnson M, Pierce RC, Bardo MT. Transient increases in catecholaminergic activity in medial prefrontal cortex and nucleus accumbens shell during novelty. Neuroscience. 1997b;76:707–714. [PubMed]
- Rivalan M, Ahmed SH, Dellu-Hagedorn F. Risk-prone individuals prefer the wrong options on a rat version of the Iowa Gambling Task. Biol Psychiatry. 2009;66:743–749. [PubMed]
- Roberts DC, Morgan D, Liu Y. How to make a rat addicted to cocaine. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1614–1624. [PMC free article] [PubMed]
- Robinson DL, Carelli RM. Distinct subsets of nucleus accumbens neurons encode operant responding for ethanol versus water. Eur J Neurosci. 2008;28:1887–1894. [PMC free article] [PubMed]
- Robinson TE, Becker JB. Behavioral sensitization is accompanied by an enhancement in amphetamine-stimulated dopamine release from striatal tissue in vitro. Eur J Pharmacol. 1982;85:253–254. [PubMed]
- Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev. 1993;18:247–291. [PubMed]
- Robinson TE, Berridge KC. Incentive-sensitization and addiction. Addiction. 2001;96:103–114. [PubMed]
- Robinson TE, Berridge KC. Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond B Biol Sci. 2008;363:3137–3146. [PMC free article] [PubMed]
- Robinson TE, Kolb B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology. 2004;47(Suppl 1):33–46. [PubMed]
- Rogers PJ, Smit HJ. Food craving and food “addiction”: a critical review of the evidence from a biopsychosocial perspective. Pharmacol Biochem Behav. 2000;66:3–14. [PubMed]
- Rothwell NJ, Stock MJ. A role for brown adipose tissue in diet-induced thermogenesis. Nature. 1979;281:31–35. [PubMed]
- Rothwell NJ, Stock MJ. The development of obesity in animals: the role of dietary factors. Clin Endocrinol Metab. 1984;13:437–449. [PubMed]
- Routtenberg A. “Self-starvation” of rats living in activity wheels: adaptation effects. J Comp Physiol Psychol. 1968;66:234–238. [PubMed]
- Routtenberg A, Kuznesof AW. Self-starvation of rats living in activity wheels on a restricted feeding schedule. J Comp Physiol Psychol. 1967;64:414–421. [PubMed]
- Russo SJ, Dietz DM, Dumitriu D, Morrison JH, Malenka RC, Nestler EJ. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 2010;33:267–276. [PMC free article] [PubMed]
- Rylkova D, Shah HP, Small E, Bruijnzeel AW. Deficit in brain reward function and acute and protracted anxiety-like behavior after discontinuation of a chronic alcohol liquid diet in rats. Psychopharmacology (Berl) 2009;203:629–640. [PMC free article] [PubMed]
- Saal D, Dong Y, Bonci A, Malenka RC. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron. 2003;37:577–582. [PubMed]
- Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–1115. [PubMed]
- Sarnyai Z, Shaham Y, Heinrichs SC. The role of corticotropin-releasing factor in drug addiction. Pharmacol Rev. 2001;53:209–243. [PubMed]
- Schaffer SD, Zimmerman ML. The sexual addict: a challenge for the primary care provider. Nurse Practitioner. 1990;15:25–26. see comment. [PubMed]
- Schramm-Sapyta NL, Olsen CM, Winder DG. Cocaine self-administration reduces excitatory responses in the mouse nucleus accumbens shell. Neuropsychopharmacology. 2006;31:1444–1451. [PubMed]
- Schulteis G, Markou A, Cole M, Koob GF. Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci U S A. 1995;92:5880–5884. [PMC free article] [PubMed]
- Schwarz L, Kindermann W. Changes in beta-endorphin levels in response to aerobic and anaerobic exercise. Sports Med. 1992;13:25–36. [PubMed]
- Segal DS, Mandell AJ. Long-term administration of d-amphetamine: progressive augmentation of motor activity and stereotypy. Pharmacol Biochem Behav. 1974;2:249–255. [PubMed]
- Segovia G, Del Arco A, De Blas M, Garrido P, Mora F. Environmental enrichment increases the in vivo extracellular concentration of dopamine in the nucleus accumbens: a microdialysis study. J Neural Transm. 2010 [PubMed]
- Self DW, Nestler EJ. Molecular mechanisms of drug reinforcement and addiction. Annu Rev Neurosci. 1995;18:463–495. [PubMed]
- Shaham Y, Shalev U, Lu L, De Wit H, Stewart J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology. 2003;168:3–20. see comment. [PubMed]
- Shalev U, Tylor A, Schuster K, Frate C, Tobin S, Woodside B. Long-term physiological and behavioral effects of exposure to a highly palatable diet during the perinatal and post-weaning periods. Physiol Behav. 2010 [PubMed]
- Shippenberg TS, Heidbreder C. Sensitization to the conditioned rewarding effects of cocaine: pharmacological and temporal characteristics. J Pharmacol Exp Ther. 1995;273:808–815. [PubMed]
- Simpson DM, Annau Z. Behavioral withdrawal following several psychoactive drugs. Pharmacol Biochem Behav. 1977;7:59–64. [PubMed]
- Sinclair JD, Senter RJ. Development of an alcohol-deprivation effect in rats. Q J Stud Alcohol. 1968;29:863–867. [PubMed]
- Skinner BF. On the Conditions of Elicitation of Certain Eating Reflexes. Proc Natl Acad Sci U S A. 1930;16:433–438. [PMC free article] [PubMed]
- Smith GB, Heynen AJ, Bear MF. Bidirectional synaptic mechanisms of ocular dominance plasticity in visual cortex. Philos Trans R Soc Lond B Biol Sci. 2009;364:357–367. [PMC free article] [PubMed]
- Smith MA, Schmidt KT, Iordanou JC, Mustroph ML. Aerobic exercise decreases the positive-reinforcing effects of cocaine. Drug Alcohol Depend. 2008;98:129–135. [PMC free article] [PubMed]
- Solecki W, Ziolkowska B, Krowka T, Gieryk A, Filip M, Przewlocki R. Alterations of prodynorphin gene expression in the rat mesocorticolimbic system during heroin self-administration. Brain Res. 2009;1255:113–121. [PubMed]
- Solinas M, Chauvet C, Thiriet N, El Rawas R, Jaber M. Reversal of cocaine addiction by environmental enrichment. Proc Natl Acad Sci U S A. 2008;105:17145–17150. [PMC free article] [PubMed]
- Solinas M, Thiriet N, Chauvet C, Jaber M. Prevention and treatment of drug addiction by environmental enrichment. Prog Neurobiol. 2010 [PubMed]
- Solinas M, Thiriet N, El Rawas R, Lardeux V, Jaber M. Environmental enrichment during early stages of life reduces the behavioral, neurochemical, and molecular effects of cocaine. Neuropsychopharmacology. 2009;34:1102–1111. [PubMed]
- Solomon RL. The opponent-process theory of acquired motivation: the costs of pleasure and the benefits of pain. Am Psychol. 1980;35:691–712. [PubMed]
- Solomon RL, Corbit JD. An opponent-process theory of motivation. I. Temporal dynamics of affect. Psychol Rev. 1974;81:119–145. [PubMed]
- Spanagel R, Holter SM. Long-term alcohol self-administration with repeated alcohol deprivation phases: an animal model of alcoholism? Alcohol Alcohol. 1999;34:231–243. [PubMed]
- Spangler R, Goddard NL, Avena NM, Hoebel BG, Leibowitz SF. Elevated D3 dopamine receptor mRNA in dopaminergic and dopaminoceptive regions of the rat brain in response to morphine. Brain Res Mol Brain Res. 2003;111:74–83. [PubMed]
- Spangler R, Wittkowski KM, Goddard NL, Avena NM, Hoebel BG, Leibowitz SF. Opiate-like effects of sugar on gene expression in reward areas of the rat brain. Brain Res Mol Brain Res. 2004;124:134–142. [PubMed]
- Spires TL, Hannan AJ. Nature, nurture and neurology: gene-environment interactions in neurodegenerative disease. FEBS Anniversary Prize Lecture delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw. FEBS J. 2005;272:2347–2361. [PubMed]
- St Onge JR, Floresco SB. Dopaminergic modulation of risk-based decision making. Neuropsychopharmacology. 2009;34:681–697. [PubMed]
- Stairs DJ, Bardo MT. Neurobehavioral effects of environmental enrichment and drug abuse vulnerability. Pharmacol Biochem Behav. 2009;92:377–382. [PMC free article] [PubMed]
- Steiner H, Gerfen CR. Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior. Exp Brain Res. 1998;123:60–76. [PubMed]
- Stewart J. Reinforcing effects of light as a function of intensity and reinforcement schedule. Journal of comparative and physiological psychology. 1960;53:187–193. [PubMed]
- Stewart J. Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. J Psychiatry Neurosci. 2000;25:125–136. [PMC free article] [PubMed]
- Stuber GD, Hopf FW, Hahn J, Cho SL, Guillory A, Bonci A. Voluntary Ethanol Intake Enhances Excitatory Synaptic Strength in the Ventral Tegmental Area. Alcohol Clin Exp Res. 2008a [PMC free article] [PubMed]
- Stuber GD, Klanker M, de Ridder B, Bowers MS, Joosten RN, Feenstra MG, et al. Reward-Predictive Cues Enhance Excitatory Synaptic Strength onto Midbrain Dopamine Neurons. Science. 2008b;321:1690–1692. [PMC free article] [PubMed]
- Tao R, Huang X, Wang J, Zhang H, Zhang Y, Li M. Proposed diagnostic criteria for internet addiction. Addiction. 2010;105:556–564. [PubMed]
- Teegarden SL, Bale TL. Decreases in dietary preference produce increased emotionality and risk for dietary relapse. Biol Psychiatry. 2007;61:1021–1029. Epub 2007 Jan 1017. [PubMed]
- Tejeiro Salguero RA, Moran RM. Measuring problem video game playing in adolescents. Addiction. 2002;97:1601–1606. [PubMed]
- Thanos PK, Tucci A, Stamos J, Robison L, Wang GJ, Anderson BJ, et al. Chronic forced exercise during adolescence decreases cocaine conditioned place preference in Lewis rats. Behav Brain Res. 2010;215:77–82. [PMC free article] [PubMed]
- Thiel KJ, Engelhardt B, Hood LE, Peartree NA, Neisewander JL. The interactive effects of environmental enrichment and extinction interventions in attenuating cue-elicited cocaine-seeking behavior in rats. Pharmacol Biochem Behav. 2011;97:595–602. [PMC free article] [PubMed]
- Thiel KJ, Sanabria F, Pentkowski NS, Neisewander JL. Anti-craving effects of environmental enrichment. Int J Neuropsychopharmacol. 2009;12:1151–1156. [PMC free article] [PubMed]
- Thomas MJ, Kalivas PW, Shaham Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br J Pharmacol. 2008;154:327–342. [PMC free article] [PubMed]
- Turchan J, Przewlocka B, Toth G, Lason W, Borsodi A, Przewlocki R. The effect of repeated administration of morphine, cocaine and ethanol on mu and delta opioid receptor density in the nucleus accumbens and striatum of the rat. Neuroscience. 1999;91:971–977. [PubMed]
- Tzschentke TM. Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol. 2007;12:227–462. [PubMed]
- Uhlrich DJ, Manning KA, O’Laughlin ML, Lytton WW. Photic-induced sensitization: acquisition of an augmenting spike-wave response in the adult rat through repeated strobe exposure. J Neurophysiol. 2005;94:3925–3937. [PubMed]
- Unterwald EM, Ho A, Rubenfeld JM, Kreek MJ. Time course of the development of behavioral sensitization and dopamine receptor up-regulation during binge cocaine administration. J Pharmacol Exp Ther. 1994a;270:1387–1396. [PubMed]
- Unterwald EM, Rubenfeld JM, Kreek MJ. Repeated cocaine administration upregulates kappa and mu, but not delta, opioid receptors. Neuroreport. 1994b;5:1613–1616. [PubMed]
- Valjent E, Pages C, Herve D, Girault JA, Caboche J. Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci. 2004;19:1826–1836. [PubMed]
- Van de Weerd HA, Van Loo PLP, Van Zutphen LFM, Koolhaas JM, Baumans V. Strength of preference for nesting material as environmental enrichment for laboratory mice. Applied Animal Behaviour Science. 1998;55:369–382.
- van den Bos R, Lasthuis W, den Heijer E, van der Harst J, Spruijt B. Toward a rodent model of the Iowa gambling task. Behav Res Methods. 2006;38:470–478. [PubMed]
- van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 1999;96:13427–13431. [PMC free article] [PubMed]
- van Praag H, Kempermann G, Gage FH. Neural consequences of enviromental enrichment. Nat Rev Neurosci. 2000a;1:191–198. [PubMed]
- van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci. 2000b;1:191–198. [PubMed]
- Vezina P, Giovino AA, Wise RA, Stewart J. Environment-specific cross-sensitization between the locomotor activating effects of morphine and amphetamine. Pharmacol Biochem Behav. 1989;32:581–584. [PubMed]
- Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse. 1993;14:169–177. [PubMed]
- Volkow ND, Fowler JS, Wang GJ, Swanson JM. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Molecular Psychiatry. 2004;9:557–569. [PubMed]
- Volkow ND, Fowler JS, Wolf AP, Schlyer D, Shiue CY, Alpert R, et al. Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry. 1990;147:719–724. [PubMed]
- Volkow ND, Wang GJ, Fowler JS, Logan J, Hitzemann R, Ding YS, et al. Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res. 1996;20:1594–1598. [PubMed]
- Volkow ND, Wise RA. How can drug addiction help us understand obesity? Nature Neuroscience. 2005;8:555–560. [PubMed]
- Vucetic Z, Kimmel J, Totoki K, Hollenbeck E, Reyes TM. Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology. 2010;151:4756–4764. [PMC free article] [PubMed]
- Wallace DL, Vialou V, Rios L, Carle-Florence TL, Chakravarty S, Kumar A, et al. The influence of DeltaFosB in the nucleus accumbens on natural reward-related behavior. J Neurosci. 2008;28:10272–10277. [PMC free article] [PubMed]
- Wanat MJ, Sparta DR, Hopf FW, Bowers MS, Melis M, Bonci A. Strain specific synaptic modifications on ventral tegmental area dopamine neurons after ethanol exposure. Biol Psychiatry. 2009a;65:646–653. [PMC free article] [PubMed]
- Wanat MJ, Willuhn I, Clark JJ, Phillips PE. Phasic dopamine release in appetitive behaviors and drug addiction. Curr Drug Abuse Rev. 2009b;2:195–213. [PMC free article] [PubMed]
- Wang GJ, Volkow ND, Telang F, Jayne M, Ma J, Rao M, et al. Exposure to appetitive food stimuli markedly activates the human brain. Neuroimage. 2004a;21:1790–1797. [PubMed]
- Wang GJ, Volkow ND, Thanos PK, Fowler JS. Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review. Journal of Addictive Diseases. 2004b;23:39–53. [PubMed]
- Ward SJ, Walker EA, Dykstra LA. Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure[reg] and Corn-Oil Seeking in Mice. Neuropsychopharmacology. 2007;32:2592–2600. [PubMed]
- Wee S, Koob GF. The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology (Berl) 2010;210:121–135. [PMC free article] [PubMed]
- Weiss F, Markou A, Lorang MT, Koob GF. Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration. Brain Res. 1992;593:314–318. [PubMed]
- Welte J, Barnes G, Wieczorek W, Tidwell MC, Parker J. Alcohol and gambling pathology among U.S. adults: prevalence, demographic patterns and comorbidity. Journal of Studies on Alcohol. 2001;62:706–712. [PubMed]
- Werme M, Messer C, Olson L, Gilden L, Thoren P, Nestler EJ, et al. Delta FosB regulates wheel running. J Neurosci. 2002;22:8133–8138. [PubMed]
- Werme M, Thoren P, Olson L, Brene S. Running and cocaine both upregulate dynorphin mRNA in medial caudate putamen. Eur J Neurosci. 2000;12:2967–2974. [PubMed]
- Winder DG, Egli RE, Schramm NL, Matthews RT. Synaptic plasticity in drug reward circuitry. Curr Mol Med. 2002;2:667–676. [PubMed]
- Winstanley CA. The orbitofrontal cortex, impulsivity, and addiction: probing orbitofrontal dysfunction at the neural, neurochemical, and molecular level. Ann N Y Acad Sci. 2007;1121:639–655. [PubMed]
- Winstanley CA. Gambling rats: insight into impulsive and addictive behavior. Neuropsychopharmacology. 2011;36:359. [PMC free article] [PubMed]
- Winstanley CA, Cocker PJ, Rogers RD. Dopamine Modulates Reward Expectancy During Performance of a Slot Machine Task in Rats: Evidence for a `Near-miss’ Effect. Neuropsychopharmacology. 2011 [PMC free article] [PubMed]
- Winstanley CA, Olausson P, Taylor JR, Jentsch JD. Insight into the relationship between impulsivity and substance abuse from studies using animal models. Alcohol Clin Exp Res. 2010;34:1306–1318. [PMC free article] [PubMed]
- Wise RA. Dopamine and reward: the anhedonia hypothesis 30 years on. Neurotox Res. 2008;14:169–183. [PMC free article] [PubMed]
- Wise RA, Munn E. Withdrawal from chronic amphetamine elevates baseline intracranial self-stimulation thresholds. Psychopharmacology (Berl) 1995;117:130–136. [PubMed]
- Wojnicki FH, Roberts DC, Corwin RL. Effects of baclofen on operant performance for food pellets and vegetable shortening after a history of binge-type behavior in non-food deprived rats. Pharmacol Biochem Behav. 2006;84:197–206. [PMC free article] [PubMed]
- Wood DA, Rebec GV. Dissociation of core and shell single-unit activity in the nucleus accumbens in free-choice novelty. Behav Brain Res. 2004;152:59–66. [PubMed]
- Young KS. Internet Addiction: The Emergence of a New Clinical Disorder. CyberPsychology & Behavior. 1998;1:237–244.
- Zeeb FD, Robbins TW, Winstanley CA. Serotonergic and dopaminergic modulation of gambling behavior as assessed using a novel rat gambling task. Neuropsychopharmacology. 2009;34:2329–2343. [PubMed]
- Zhu J, Apparsundaram S, Bardo MT, Dwoskin LP. Environmental enrichment decreases cell surface expression of the dopamine transporter in rat medial prefrontal cortex. J Neurochem. 2005;93:1434–1443. [PubMed]
- Zijlstra F, Booij J, van den Brink W, Franken IH. Striatal dopamine D2 receptor binding and dopamine release during cue-elicited craving in recently abstinent opiate-dependent males. Eur Neuropsychopharmacol. 2008;18:262–270. [PubMed]
- Zlebnik NE, Anker JJ, Gliddon LA, Carroll ME. Reduction of extinction and reinstatement of cocaine seeking by wheel running in female rats. Psychopharmacology (Berl) 2010;209:113–125. [PMC free article] [PubMed]
- Zuckerman M. Sensation seeking and the endogenous deficit theory of drug abuse. NIDA Research Monograph. 1986;74:59–70. [PubMed]
- Zuckerman M. Sensation seeking: The balance between risk and reward. In: Lipsitt L, Mitnick L, editors. Self-Regulatory Behavior and Risk-Taking: Causes and Consequences. Ablex Publishing Corporation; Norwood, NJ: 1991. pp. 143–152.