George F. Koob, Ph.D.
Drug addiction can be defined by a compulsion to seek and take drug, loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug is prevented. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in reward and stress within the basal forebrain structures involving the ventral striatum and extended amygdala. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreases in dopamine and opioid peptide function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, increases in anxiety-like responses, and increases in extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of addiction. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include norepinephrine, dynorphin, and neuropeptide Y. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement driving, at least in part, the compulsivity of addiction.
1. Definitions and conceptual framework for compulsivity in addiction
Drug addiction is a chronically relapsing disorder characterized by (i) compulsion to seek and take the drug, (ii) loss of control in limiting intake, and (iii) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented (defined here as dependence) (Koob and Le Moal, 1997). Addiction is assumed to be identical to the syndrome of Substance Dependence (as currently defined by the Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1994). Clinically and in animal models, the occasional but limited use of a drug with the potential for abuse or dependence is distinct from escalated drug intake and the emergence of a chronic drug-dependent state.
Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity, where impulsivity can be defined behaviorally as “a predisposition toward rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to themselves or others” (Moeller et al., 2001). Impulsivity is measured in two domains: the choice of a smaller, immediate reward over a larger, delayed reward (Rachlin and Green, 1972) or the inability to inhibit behavior by changing the course of action or to stop a response once it is initiated (Logan et al., 1997). Impulsivity is a core deficit in substance abuse disorders (Allen et al., 1998) and in neuropsychiatric disorders such as attention deficit hyperactivity disorder. Operationally, delay-to-gratification tasks (delayed discounting tasks) (impulsive choice) and the stop-signal or go/no-go task (behavioral impulsivity) have been used as measures of impulsivity (Fillmore and Rush, 2002; Green et al., 1994). Compulsivity can be defined as elements of behavior that result in perseveration in responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations. These elements are analogous to the symptoms of Substance Dependence as outlined by the American Psychiatric Association: continued substance use despite knowledge of having had a persistent or recurrent physical or psychological problem and a great deal of time spent in activities necessary to obtain the substance (American Psychiatric Association, 2000).
Collapsing the cycles of impulsivity and compulsivity yields a composite addiction cycle comprised of three stages—preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect—where impulsivity often dominates at the early stages and compulsivity dominates at terminal stages. As an individual moves from impulsivity to compulsivity, a shift occurs from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior (Koob, 2004). Negative reinforcement can be defined as the process by which removal of an aversive stimulus (e.g., negative emotional state of drug withdrawal) increases the probability of a response (e.g., dependence-induced drug intake). These three stages are conceptualized as interacting with each other, becoming more intense, and ultimately leading to the pathological state known as addiction (Koob and Le Moal, 1997) (Table 1). The present review will focus on the role of an animal model of compulsivity that derives from the negative emotional state of the withdrawal/negative affect stage of the addiction cycle.
Different drugs produce different patterns of addiction with emphasis on different components of the addiction cycle. Opioids can be considered classic drugs of addiction because subjects meet most of the criteria classically associated with addiction, including dramatic tolerance and withdrawal. A pattern of intravenous or smoked drug-taking evolves, including intense intoxication, the development of tolerance, escalation in intake, and profound dysphoria, physical discomfort, and somatic withdrawal signs during abstinence. Intense preoccupation with obtaining opioids (craving) develops that often precedes the somatic signs of withdrawal and is linked not only to stimuli associated with obtaining the drug but also to stimuli associated with withdrawal and the aversive motivational state. A pattern develops where the drug must be obtained to avoid the severe dysphoria and discomfort of abstinence. Other drugs of abuse follow a similar pattern but may involve more the binge/intoxication stage (psychostimulants and alcohol) or less binge/intoxication and more withdrawal/negative affect and preoccupation/anticipation stages (nicotine and cannabinoids).
Alcohol addiction, or alcoholism, can follow a similar trajectory, but the pattern of oral drug taking is often characterized by binges of alcohol intake that can be daily episodes or prolonged days of heavy drinking and is characterized by a severe emotional and somatic withdrawal syndrome. Many alcoholics continue with such a binge/withdrawal pattern for extended periods, but some individuals can evolve into an opioid-like situation in which they must have alcohol available at all times to avoid the negative consequences of abstinence. Tobacco addiction contrasts with the above patterns—the binge/intoxication stage forms a minor component of nicotine dependence. The pattern of nicotine intake is one of highly titrated intake of the drug except during periods of sleep. However, during abstinence, users experience negative emotional states, including dysphoria, irritability, and intense craving. Marijuana Dependence follows a pattern similar to opioids and tobacco, with a significant intoxication stage, but as chronic use continues, subjects begin to show a pattern of use manifest by chronic intoxication during waking hours and withdrawal characterized by dysphoria, irritability, and sleep disturbances. Psychostimulants, such as cocaine and amphetamines, show a pattern focused on the binge/intoxication stage in which binges can be hours or days in duration and often are followed by a withdrawal (“crash”) characterized by extreme dysphoria and inactivity.
1.1. Motivation, withdrawal, and opponent process
Motivation is a state that can be defined as a “tendency of the whole animal to produce organized activity” (Hebb, 1972), and such motivational states are not constant but rather vary over time. Early work by Wikler stressed the role of changes in drive states associated with dependence. Subjects described withdrawal changes as a “hunger” or primary need and the effects of morphine on such a state as “satiation” or gratification of the primary need (Wikler, 1952). Although Wikler argued that positive reinforcement was retained even in heavily dependent subjects (thrill of the intravenous opioid injection), dependence produced a new source of gratification, that of negative reinforcement (see above).
The concept of motivation was linked inextricably with hedonic, affective, or emotional states in addiction in the context of temporal dynamics by Solomon’s opponent process theory of motivation. Solomon and Corbit (1974) postulated that hedonic, affective, or emotional states, once initiated, are automatically modulated by the central nervous system with mechanisms that reduce the intensity of hedonic feelings. The a-process includes affective or hedonic habituation (or tolerance), and the b-process includes affective or hedonic withdrawal (abstinence). The a-process in drug use consists of positive hedonic responses, occurs shortly after presentation of a stimulus, correlates closely with the intensity, quality, and duration of the reinforcer, and shows tolerance. In contrast, the b-process in drug use appears after the a-process has terminated, consists of negative hedonic responses, and is sluggish in onset, slow to build up to an asymptote, slow to decay, and gets larger with repeated exposure. The thesis here is that opponent processes begin early in drug-taking, reflect changes in the brain reward and stress systems, and later form one of the major motivations for compulsivity in drug taking.
Thus, dependence or manifestation of a withdrawal syndrome after removal of chronic drug administration is defined in terms of motivational aspects of dependence such as emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented (Koob and Le Moal, 2001), rather than on the physical signs of dependence. Indeed, some have argued that the development of such a negative affective state can define dependence as it relates to addiction:
“The notion of dependence on a drug, object, role, activity or any other stimulus-source requires the crucial feature of negative affect experienced in its absence. The degree of dependence can be equated with the amount of this negative affect, which may range from mild discomfort to extreme distress, or it may be equated with the amount of difficulty or effort required to do without the drug, object, etc” (Russell, 1976).
Rapid acute tolerance and opponent process-like effects in response to the hedonic effects of cocaine have been reported in human studies of smoked coca paste (Van Dyke and Byck, 1982) (Figure 1A). After a single smoking session, the onset and intensity of the “high” are very rapid via the smoked route of administration, and a rapid tolerance is manifest. The “high” decreases rapidly despite significant blood levels of cocaine. Even more intriguing is that human subjects also actually report a subsequent “dysphoria,” again despite high blood levels of cocaine. Intravenous cocaine produced similar patterns of a rapid “rush” followed by an increased “low” in human laboratory studies (Breiter et al., 1997) (Figure 1B). With intravenous cocaine self-administration in animal models, such elevations in reward threshold begin rapidly and can be observed within a single session of self-administration (Kenny et al., 2003) (Figure 2), bearing a striking resemblance to human subjective reports. These results demonstrate that the elevation in brain reward thresholds following prolonged access to cocaine failed to return to baseline levels between repeated, prolonged exposure to cocaine self-administration (i.e., residual hysteresis), thus creating a greater and greater elevation in “baseline” ICSS thresholds. These data provide compelling evidence for brain reward dysfunction in escalated cocaine self-administration that provide strong support for a hedonic allostasis model of drug addiction.
Similar results have been observed showing dysphoria-like responses accompanying acute opioid and ethanol withdrawal (Liu and Schulteis, 2004; Schulteis and Liu, 2006). Here, naloxone administration following single injections of morphine increased reward thresholds, measured by ICSS, and increased thresholds with repeated morphine and naloxone-induced withdrawal experience (Liu and Schulteis, 2004). Similar results were observed during repeated acute withdrawal from ethanol (Schulteis and Liu, 2006).
The dysregulation of brain reward function associated with withdrawal from chronic administration of drugs of abuse is a common element of all drugs of abuse. Withdrawal from chronic cocaine (Markou and Koob, 1991), amphetamine (Paterson et al., 2000), opioids (Schulteis et al., 1994), cannabinoids (Gardner and Vorel, 1998), nicotine (Epping-Jordan et al., 1998), and ethanol (Schulteis et al., 1995) leads to increases in reward threshold during acute abstinence, and some of these elevations in threshold can last for up to one week (Figure 3). These observations lend credence to the hypothesis that opponent processes can set the stage for one aspect of compulsivity where negative reinforcement mechanisms are engaged.
More recently, opponent process theory has been expanded into the domains of the neurobiology of drug addiction from a neurocircuitry perspective. An allostatic model of the brain motivational systems has been proposed to explain the persistent changes in motivation that are associated with dependence in addiction (Koob and Le Moal 2001, 2008). In this formulation, addiction is conceptualized as a cycle of increasing dysregulation of brain reward/anti-reward mechanisms that results in a negative emotional state contributing to the compulsive use of drugs. Counteradaptive processes that are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range. These counteradaptive processes are hypothesized to be mediated by two mechanisms: within-system neuroadaptations and between-system neuroadaptations (Koob and Bloom, 1988).
In a within-system neuroadaptation, “the primary cellular response element to the drug would itself adapt to neutralize the drug’s effects; persistence of the opposing effects after the drug disappears would produce the withdrawal response” (Koob and Bloom, 1988). Thus, a within-system neuroadaptation is a molecular or cellular change within a given reward circuit to accommodate overactivity of hedonic processing associated with addiction resulting in a decrease in reward function.
The emotional dysregulation associated with the withdrawal/negative affect stage also may involve between-system neuroadaptations in which neurochemical systems other than those involved in the positive rewarding effects of drugs of abuse are recruited or dysregulated by chronic activation of the reward system (Koob and Bloom, 1988). Thus, a between-system neuroadaptation is a circuitry change in which another different circuit (anti-reward circuit) is activated by the reward circuit and has opposing actions, again limiting reward function. The purpose of this review is to explore the neuroadaptational changes that occur in the brain emotional systems to account for the neurocircuitry changes that produce opponent processes and are hypothesized to have a key role in the compulsivity of addiction.
1.2. Animal models of compulsivity in addiction measured by negative emotional-like states: Place aversion, animal models of anxiety, and reward thresholds
Animal models of the withdrawal/negative affect stage include measures of conditioned place aversion (rather than preference) to precipitated withdrawal or spontaneous withdrawal from chronic administration of a drug, increases in reward thresholds using brain stimulation reward (Markou and Koob, 1991; Schulteis et al., 1994, 1995; Epping-Jordan et al., 1998; Gardner and Vorel, 1998; Paterson et al., 2000), and increases in anxiety-like responses (for review, see Shippenberg and Koob, 2002; Sanchis-Segura and Spanagel, 2006).
1.3. Animal models of compulsivity in addiction as defined by increased drug taking: Escalation in drug self-administration with prolonged access
A progressive increase in the frequency and intensity of drug use is one of the major behavioral phenomena characterizing the development of addiction and has face validity with the criteria of the Diagnostic and Statistical Manual of Mental Disorders: “The substance is often taken in larger amounts and over a longer period than was intended” (American Psychological Association, 1994). A framework with which to model the transition from drug use to drug addiction can be found in recent animal models of prolonged access to intravenous cocaine self-administration. Historically, animal models of cocaine self-administration involved the establishment of stable behavior from day to day to allow the reliable interpretation of data provided by within-subject designs aimed at exploring the neuropharmacological and neurobiological bases of the reinforcing effects of acute cocaine. Up until 1998, after acquisition of self-administration, rats typically were allowed access to cocaine for 3 h or less per day to establish highly stable levels of intake and patterns of responding between daily sessions. This was a useful paradigm for exploring the neurobiological substrates for the acute reinforcing effects of drugs of abuse.
However, in an effort to explore the possibility that differential access to intravenous cocaine self-administration in rats may produce different patterns of drug intake, rats were allowed access to intravenously self-administration cocaine for 1 or 6 h per day (Ahmed and Koob, 1998). One hour access (short access or ShA) to intravenous cocaine per session produced low and stable intake as observed previously. In contrast, 6 h access (long access or LgA) to cocaine produced drug intake that gradually escalated over days (Figure 4). Increased intake was observed in the extended access group during the first hour of the session, with sustained intake over the entire session and an upward shift in the dose-effect function, suggesting an increase in hedonic set point. When animals were allowed access to different doses of cocaine, both the LgA and ShA animals titrated their cocaine intake, but the LgA rats consistently self-administered almost twice as much cocaine at any dose tested, further suggesting an upward shift in the set point for cocaine reward in the escalated animals (Ahmed and Koob, 1999; Deroche-Gamonet et al., 2004; Mantsch et al., 2004). Escalation also is associated with an increase in break point for cocaine in a progressive-ratio schedule of reinforcement, suggesting an enhanced motivation to seek cocaine or an enhanced efficacy of cocaine reward (Paterson and Markou, 2003; Wee et al., 2008). Such increased self-administration in dependent animals has now been observed with cocaine, methamphetamine, nicotine, heroin, and alcohol (Ahmed et al., 2000; Ahmed and Koob, 1998; Kitamura et al., 2006; O’Dell et al., 2004; George et al., 2007) (Figure 4). This model is a key element for evaluating the motivational significance of opponent process changes in the brain reward and stress systems in addiction that lead to compulsivity in addiction. Similar changes in the reinforcing and incentive effects of cocaine as drug intake have been observed following extended access and include increased cocaine-induced reinstatement after extinction and a decreased latency to goal time in a runway model for cocaine reward (Deroche et al., 1999). Altogether, these results suggest that drug taking with extended access changes the motivation to seek the drug. Whether this enhanced drug taking reflects a sensitization of reward or a reward deficit state remains under discussion (Vezina, 2004), but the brain reward and neuropharmacological studies outlined below argue for a reward deficit state driving the increased drug taking during extended access.
The hypothesis that compulsive cocaine use is accompanied by a chronic perturbation in brain reward homeostasis has been tested in an animal model of escalation in drug intake with prolonged access combined with measures of brain stimulation reward thresholds. Animals implanted with intravenous catheters and allowed differential access to intravenous self-administration of cocaine showed increases in cocaine self-administration from day to day in the long-access group (6 h; LgA) but not in the short-access group (1 h; ShA). The differential exposure to cocaine self-administration had dramatic effects on reward thresholds that progressively increased in LgA rats but not in ShA or control rats across successive self-administration sessions (Ahmed et al., 2002). Elevation in baseline reward thresholds temporally preceded and was highly correlated with escalation in cocaine intake (Figure 5). Post-session elevations in reward thresholds failed to return to baseline levels before the onset of each subsequent self-administration session, thereby deviating more and more from control levels. The progressive elevation in reward thresholds was associated with the dramatic escalation in cocaine consumption that was observed previously. After escalation had occurred, an acute cocaine challenge facilitated brain reward responsiveness to the same degree as before but resulted in higher absolute brain reward thresholds in LgA compared with ShA rats (Ahmed et al., 2002). Similar results have been observed with extended access to heroin (Kenny et al., 2006). Rats allowed 23 h access to heroin also showed a time-dependent increase in reward thresholds that paralleled the increases in heroin intake (Figure 5).
2. Neural substrates for the negative emotional state associated with addiction
2.1. Within-system neuroadaptations that contribute to the negative emotional state component of compulsivity
Electrical brain stimulation reward or intracranial self-stimulation has a long history as a measure of activity of the brain reward system and of the acute reinforcing effects of drugs of abuse. All drugs of abuse, when administered acutely, decrease brain stimulation reward thresholds (Kornetsky and Esposito, 1979) and when administered chronically increase reward thresholds during withdrawal (see above). Brain stimulation reward involves widespread neurocircuitry in the brain, but the most sensitive sites defined by the lowest thresholds involve the trajectory of the medial forebrain bundle that connects the ventral tegmental area with the basal forebrain (Olds and Milner, 1954; Koob et al., 1977). While much emphasis was focused initially on the role of the ascending monoamine systems in the medial forebrain bundle, other nondopaminergic systems in the medial forebrain bundle clearly have a key role (Hernandez et al., 2006).
Within-system neuroadaptations to chronic drug exposure include decreases in function of the same neurotransmitter systems in the same neurocircuits implicated in the acute reinforcing effects of drugs of abuse. One prominent hypothesis is that dopamine systems are compromised in crucial phases of the addiction cycle, such as withdrawal and leads to decreased motivation for non-drug-related stimuli and increased sensitivity to the abused drug (Melis et al., 2005). Activation of the mesolimbic dopamine system has long been known to be critical for the acute rewarding properties of psychostimulant drugs and to be associated with the acute reinforcing effects of other drugs of abuse (Koob, 1992; Di Chiara and North, 1992; Nestler, 2005). Decreases in activity of the mesolimbic dopamine system and decreases in serotonergic neurotransmission in the nucleus accumbens occur during drug withdrawal in animal studies (Rossetti et al., 1992; Weiss et al., 1992, 1996). Imaging studies in drug-addicted humans have consistently shown long-lasting decreases in the numbers of dopamine D2 receptors in drug abusers compared with controls (Volkow et al., 2002). In addition, cocaine abusers have reduced dopamine release in response to a pharmacological challenge with a stimulant drug (Volkow et al., 1997; Martinez et al., 2007). Decreases in the number of dopamine D2 receptors, coupled with the decrease in dopaminergic activity, in cocaine, nicotine, and alcohol abusers results in decreased sensitivity of reward circuits to stimulation by natural reinforcers (Martin-Solch et al., 2001; Volkow and Fowler, 2000). These findings suggest an overall reduction in the sensitivity of the dopamine component of reward circuitry to natural reinforcers and other drugs in drug-addicted individuals.
Psychostimulant withdrawal in humans is associated with fatigue, decreased mood, and psychomotor retardation and in animals is associated with decreased motivation to work for natural rewards (Barr and Phillips, 1999) and decreased locomotor activity (Pulvirenti and Koob, 1993), behavioral effects that may involve decreased dopaminergic function. Animals during amphetamine withdrawal show decreased responding on a progressive-ratio schedule for a sweet solution, and this decreased responding was reversed by the dopamine partial agonist terguride (Orsini et al., 2001), suggesting that low dopamine tone contributes to the motivational deficits associated with psychostimulant withdrawal.
Under this conceptual framework, other within-system neuroadaptations would include increased sensitivity of receptor transduction mechanisms in the nucleus accumbens. Drugs of abuse have acute receptor actions that are linked to intracellular signaling pathways that may undergo adaptations with chronic treatment. Activation of adenylate cyclase, protein kinase A, cyclic adenosine monophosphate response-element binding protein (CREB), and ΔFosB has been observed during opioid withdrawal (Self et al., 1995; Shaw-Lutchman et al., 2002; Nye and Nestler, 1996; Nestler, 2004). The ΔFosB response is hypothesized to represent a neuroadaptive change that extends long into protracted abstinence (Nestler and Malenka, 2004).
2.2. Between-system neuroadaptations that contribute to the negative emotional state component of compulsivity
Brain neurochemical systems involved in arousal-stress modulation also may be engaged within the neurocircuitry of the brain stress systems in an attempt to overcome the chronic presence of the perturbing drug and to restore normal function despite the presence of drug. Both the hypothalamic-pituitary-adrenal axis and the brain stress system mediated by corticotropin-releasing factor (CRF) are dysregulated by chronic administration of all major drugs with dependence or abuse potential, with a common response of elevated adrenocorticotropic hormone, corticosterone, and amygdala CRF during acute withdrawal (Rivier et al., 1984; Merlo-Pich et al., 1995; Koob et al., 1994; Rasmussen et al., 2000; Olive et al., 2002; Delfs et al., 2000). Acute withdrawal from all drugs of abuse also produces an aversive or anxiety-like state that can be reversed by CRF antagonists (see below).
The neuroanatomical entity termed the extended amygdala (Heimer and Alheid, 1991) may represent a common anatomical substrate integrating brain arousal-stress systems with hedonic processing systems to produce the between-system opponent process elaborated above. The extended amygdala is composed of the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial (shell) subregion of the nucleus accumbens. Each of these regions has cytoarchitectural and circuitry similarities (Heimer and Alheid, 1991). The extended amygdala receives numerous afferents from limbic structures such as the basolateral amygdala and hippocampus and sends efferents to the medial part of the ventral pallidum and a large projection to the lateral hypothalamus, thus further defining the specific brain areas that interface classical limbic (emotional) structures with the extrapyramidal motor system (Alheid et al., 1995). The extended amygdala has long been hypothesized to have a key role not only in fear conditioning (Le Doux, 2000) but also in the emotional component of pain processing (Neugebauer et al., 2004).
2.3. Neuropharmacological studies of the aversive stimulus effects of drug withdrawal
Place aversion has been used to measure the aversive stimulus effects of withdrawal, mostly in the context of opioids (Hand et al., 1988; Stinus et al., 1990). In contrast to conditioned place preference, rats exposed to a particular environment while undergoing precipitated withdrawal to opioids spend less time in the withdrawal-paired environment when subsequently presented with a choice between that environment and an unpaired environment. These aversive stimulus effects can be measured from 24 h to 16 weeks later (Hand et al., 1988; Stinus et al., 1990, 2000). The place aversion does not require maintenance of opioid dependence for its manifestation. Such an association continues to be manifested weeks after animals are “detoxified” (e.g., after the morphine pellets are removed) (see Baldwin and Koob, 1993; Stinus et al., 2000). In addition, a place aversion in opioid-dependent rats can be observed with doses of naloxone below which somatic signs of withdrawal are observed (Schulteis et al., 1994). Although naloxone itself will produce a place aversion in nondependent rats, the threshold dose required to produce a place aversion decreases significantly in dependent rats (Hand et al., 1988). A variant on this approach is to explore the place aversion produced following naloxone injection after a single acute injection of morphine.
Acute opioid dependence has been defined as the precipitation of withdrawal-like signs by opioid antagonists following a single dose or short-term administration of an opioid agonist (Martin and Eades, 1964). Rats show a reliable conditioned place aversion precipitated by a low dose of naloxone after a single morphine injection that reflects a motivational component of acute withdrawal (Azar et al., 2003). Acute opioid withdrawal also produces increases in reward thresholds (Liu and Schulteis, 2004), suppression in operant responding (Schulteis et al., 2003) and increased anxiety-like behavior in the elevated plus maze (Zhang and Schulteis, 2008). Using the conditioned place aversion paradigm, the opioid partial agonist buprenorphine dose-dependently decreased the place aversion produced by precipitated opioid withdrawal. Systemic administration of a CRF1 receptor antagonist and direct intracerebral administration of a peptide CRF1/CRF2 antagonist also decreased opioid withdrawal-induced place aversions (Stinus et al., 2005; Heinrichs et al., 1995). Functional noradrenergic antagonists blocked opioid withdrawal-induced place aversion (Delfs et al., 2000).
Another candidate for the aversive effects of drug withdrawal is dynorphin. Much evidence shows that dynorphin is increased in the nucleus accumbens in response to dopaminergic activation and, in turn, that overactivity of the dynorphin systems can decrease dopaminergic function. κ opioid agonists are aversive (Land et al., 2008; Pfeiffer et al., 1986), and cocaine, opioid, and ethanol withdrawal is associated with increased dynorphin in the nucleus accumbens and/or amygdala (Spangler et al., 1993; Lindholm et al., 2000; Rattan et al., 1992).
2.4. Neuropharmacological studies of the anxiety-like effects of drug withdrawal
Another common response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like responses. Animal models have revealed anxiety-like response to all major drugs of abuse during acute withdrawal. The dependent variable is often a passive response to a novel and/or aversive stimulus, such as the open field or elevated plus maze, or an active response to an aversive stimulus, such as defensive burying of an electrified metal probe. Withdrawal from repeated administration of cocaine produces an anxiogenic-like response in the elevated plus maze and defensive burying test, both of which are reversed by administration of CRF antagonists (Sarnyai et al., 1995; Basso et al., 1999). Precipitated withdrawal in opioid dependence also produces anxiety-like effects (Schulteis et al., 1998; Harris and Aston-Jones, 1993). Ethanol withdrawal produces anxiety-like behavior that is reversed by intracerebroventricular administration of CRF1/CRF2 peptidergic antagonists (Baldwin et al., 1991), small molecule CRF1 antagonist (Knapp et al., 2004; Overstreet et al., 2004; Funk et al., 2007), and intracerebral administration of a peptidergic CRF1/CRF2 antagonist into the amygdala (Rassnick et al., 1993). CRF antagonists injected intracerebroventricularly or systemically also block the potentiated anxiety-like responses to stressors observed during protracted abstinence from chronic ethanol (Breese et al., 2005; Valdez et al., 2003). The effects of CRF antagonists have been localized to the central nucleus of the amygdala (Rassnick et al., 1993). Precipitated withdrawal from nicotine produces anxiety-like responses that are also reversed by CRF antagonists (Tucci et al., 2003; George et al., 2007).
3. Neural Substrates for Increased Drug-taking with Extended Access
3.1. Within-system neuroadaptations
In a series of studies, dopamine partial agonists have not only been shown to reverse psychostimulant withdrawal but also to block the increase in psychostimulant self-administration associated with extended access. Dopamine partial agonists decrease the reinforcing effects of psychostimulant drugs in nondependent limited access paradigms (Izzo et al., 2001; Pulvirenti et al., 1998). However, animals with extended access show an increased sensitivity to a dopamine partial agonist (Wee et al., 2007). Long-access rats administered a dopamine D2 partial agonist showed a shift to the left of the dose-response function similar to results observed with dopamine antagonists (Ahmed and Koob, 2004). These results, combined with the observation that dopamine partial agonists also can reverse psychostimulant withdrawal, suggest that dysregulation of dopamine tone may contribute to the motivational effects of drug withdrawal.
Similar results have been observed in opioid dependence with the opioid partial agonist buprenorphine. Buprenorphine dose-dependently decreased heroin self-administration in opioid-dependent rats (Chen et al., 2006).
3.2. Between-system neuroadaptations
The ability of CRF antagonists to block the anxiogenic-like and aversive-like motivational effects of drug withdrawal would predict motivational effects of CRF antagonists in animal models of extended access to drugs. CRF antagonists selectively blocked the increased self-administration of drugs associated with extended access to intravenous self-administration of cocaine (Specio et al., 2008), nicotine (George et al., 2007), and heroin (Greenwell et al., 2008a). CRF antagonists also blocked the increased self-administration of ethanol in dependent rats (Funk et al., 2007) (Table 2).
Administration of CRF1 antagonists systemically reversed the increased self-administration of cocaine associated with extended access, and this reversal was at antagonist doses that were lower than those that decreased short-access self-administration (Specio et al., 2008). Here, rats allowed 6 h access to cocaine showed an increase in cocaine intake over time, whereas 1 h access rats remained stable. Two different CRF1 antagonists blocked cocaine self-administration in the long-access rats at doses lower than those that blocked cocaine self-administration in short-access rats (Specio et al., 2008).
As noted above, CRF in parts of the extended amygdala is involved in the aversive stimulus effects of opioid withdrawal. The selective CRF1 antagonist antalarmin blocked the place aversion produced by naloxone in morphine-dependent rats (Stinus et al., 2005). CRF1 knockout mice failed to show conditioned place aversion to opioid withdrawal and failed to show an opioid-induced increase in dynorphin mRNA in the nucleus accumbens (Contarino and Papaleo, 2005). CRF1 antagonists also selectively blocked the increase in heroin self-administration observed in heroin-dependent rats with extended access (Greenwell et al., 2008a).
Also, as noted above, precipitated withdrawal from chronic nicotine produced anxiogenic-like effects that were blocked by a CRF1 receptor antagonist (George et al., 2007) and increases in reward thresholds that were reversed by a CRF antagonist (Bruijnzeel et al., 2007). Extracellular CRF has been shown to be increased in the amygdala during withdrawal from chronic nicotine (George et al., 2007). From a developmental perspective, increased CRF-like immunoreactivity has been observed in adult rats exposed to nicotine during adolescence and has been linked to an anxiety-like phenotype (Slawecki et al., 2005). Systemic administration of a CRF1 antagonist blocked the increased self-administration of nicotine associated with withdrawal in extended access (23 h) animals (George et al., 2007). These results suggest that CRF in the basal forebrain also may have an important role in the development of the aversive motivational effects that drive the increased drug seeking associated with cocaine, heroin, and nicotine dependence.
A particularly dramatic example of the motivational effects of CRF in dependence can be observed in animal models of ethanol self-administration in dependent animals. During ethanol withdrawal, extrahypothalamic CRF systems become hyperactive, with an increase in extracellular CRF within the central nucleus of the amygdala and bed nucleus of the stria terminalis of dependent rats (Funk et al., 2006; Merlo-Pich et al., 1995; Olive et al., 2002). The dysregulation of brain CRF systems is hypothesized to underlie not only the enhanced anxiety-like behaviors but also the enhanced ethanol self-administration associated with ethanol withdrawal. Supporting this hypothesis, the -helical CRF9–41 and D-Phe CRF12–41 (intracerebroventricular administration) reduce ethanol self-administration in dependent animals (Valdez et al., 2004). Exposure to repeated cycles of chronic ethanol vapor produced substantial increases in ethanol intake in rats both during acute withdrawal and during protracted abstinence (2 weeks post-acute withdrawal) (O’Dell et al., 2004; Rimondini et al., 2002). Intracerebroventricular administration of a CRF1/CRF2 antagonist blocked the dependence-induced increase in ethanol self-administration during both acute withdrawal and protracted abstinence (Valdez et al., 2004). When administered directly into the central nucleus of the amygdala, a CRF1/CRF2 antagonist blocked ethanol self-administration in ethanol-dependent rats (Funk et al., 2006, 2007). Systemic injections of small-molecule CRF1 antagonists also blocked the increased ethanol intake associated with acute withdrawal (Knapp et al., 2004; Overstreet et al., 2004; Funk et al., 2007). These data suggest an important role for CRF, primarily within the central nucleus of the amygdala, in mediating the increased self-administration associated with dependence.
Although less well developed, evidence exists for a role of norepinephrine systems in the extended amygdala in the negative motivational state and increased self-administration associated with dependence. Norepinephrine functional antagonists (β1 antagonist and α2 agonist) injected into the lateral bed nucleus of the stria terminalis blocked precipitated opiate withdrawal-induced place aversions (Delfs et al., 2000). The effects of norepinephrine in mediating the motivational effects of opioid withdrawal involve the ventral noradrenergic system. Ventral noradrenergic bundle lesions attenuated opioid withdrawal-induced place aversions (Delfs et al., 2000), but virtually complete lesions of the dorsal noradrenergic bundle from the locus coeruleus with the neurotoxin 6-hydroxydopamine failed to block the place aversion produced by opioid withdrawal (Caille et al., 1999). Functional norepinephrine antagonists block excessive drug intake associated with dependence on ethanol (Walker et al., 2008), cocaine (Wee et al., 2008), and opioids (Greenwell et al., 2008b). A focal point for many of these effects is the extended amygdala but at the level of the bed nucleus of the stria terminalis. κ Dynorphin, an opioid peptide that binds to κ opioid receptors, has long been known to show activation with chronic administration of psychostimulants and opioids (Nestler, 2004; Koob, 2008), and κ opioid agonists produce aversive effects in animals and humans (Mucha and Herz, 1985; Pfeiffer et al., 1986). A κ opioid antagonist blocks the excessive drinking associated with ethanol withdrawal and dependence (Walker and Koob, 2008). Evidence demonstrates that κ receptor activation can produce CRF release (Song and Takemori, 1992), but recently some have argued that the effects of dynorphin in producing negative emotional states are mediated via activation of CRF systems (Land et al., 2008).
The dynamic nature of the brain stress system response to challenge is illustrated by the pronounced interaction of central nervous system CRF systems and central nervous system norepinephrine systems. Conceptualized as a feed-forward system at multiple levels of the pons and basal forebrain, CRF activates norepinephrine, and norepinephrine in turn activates CRF (Koob, 1999). Much pharmacologic, physiologic, and anatomic evidence supports an important role for a CRF-norepinephrine interaction in the region of the locus coeruleus in response to stressors (Valentino et al., 1991, 1993; Van Bockstaele et al., 1998). However, norepinephrine also stimulates CRF release in the paraventricular nucleus of the hypothalamus (Alonso et al., 1986), the bed nucleus of the stria terminalis, and the central nucleus of the amygdala. Such feed-forward systems were further hypothesized to have powerful functional significance for mobilizing an organism’s response to environmental challenge, but such a mechanism may be particularly vulnerable to pathology (Koob, 1999).
Neuropeptide Y (NPY) is a neuropeptide with dramatic anxiolytic-like properties localized to the amygdala and has been hypothesized to have opposite effects to CRF in the negative motivational state of withdrawal from drugs of abuse (Heilig and Koob, 2007). Significant evidence suggests that activation of NPY in the central nucleus of the amygdala can block the motivational aspects of dependence associated with chronic ethanol administration. NPY administered intracerebroventricularly blocked the increased drug intake associated with ethanol dependence (Thorsell et al., 2005a, b). Injection of NPY directly into the central nucleus of the amygdala (Gilpin et al., 2008) and viral vector-enhanced expression of NPY in the central nucleus of the amygdala also blocked the increased drug intake associated with ethanol dependence (Thorsell et al., 2007).
Thus, acute withdrawal from drugs increases CRF in the central nucleus of the amygdala that has motivational significance for the anxiety-like effects of acute withdrawal and the increased drug intake associated with dependence (Figure 6). Acute withdrawal also may increase the release of norepinephrine in the bed nucleus of the stria terminalis and dynorphin in the nucleus accumbens, and both of which may contribute to the negative emotional state associated with dependence. Decreased activity of NPY in the central nucleus of the amygdala also may contribute to the anxiety-like state associated with ethanol dependence. Activation of brain stress systems (CRF, norepinephrine, dynorphin) combined with inactivation of brain anti-stress systems (NPY) elicits powerful emotional dysregulation in the extended amygdala. Such dysregulation of emotional processing may be a significant contribution to the between-system opponent processes that help maintain dependence and also set the stage for more prolonged state changes in emotionality such as protracted abstinence.
4. Compulsivity in addiction: An allostatic view
Compulsivity in addiction can derive from multiple sources, including enhanced incentive salience, engagement of habit function, and impairment in executive function. However, underlying each of these sources is a negative emotional state that may strongly impact on compulsivity. The development of the negative emotional state that drives the negative reinforcement of addiction has been defined as the “dark side” of addiction (Koob and Le Moal, 2005, 2008) and is hypothesized to be the b-process of the hedonic dynamic known as opponent process when the a-process is euphoria. The negative emotional state that comprises the withdrawal/negative affect stage consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards, and is characterized in animals by increases in reward thresholds during withdrawal from all major drugs of abuse. Two processes are hypothesized to form the neurobiological basis for the b-process: loss of function in the reward systems (within-system neuroadaptation) and recruitment of the brain stress or anti-reward systems (between-system neuroadaptation) (Koob and Bloom, 1988; Koob and Le Moal, 1997). Anti-reward is a construct based on the hypothesis that brain systems are in place to limit reward (Koob and Le Moal, 2008). As dependence and withdrawal develop, brain stress systems such as CRF, norepinephrine, and dynorphin are recruited, producing aversive or stress-like states (Koob, 2003; Nestler, 2001; Aston-Jones et al., 1999). At the same time, within the motivational circuits of the ventral striatum-extended amygdala, reward function decreases. The combination of decreases in reward neurotransmitter function and recruitment of anti-reward systems provides a powerful source of negative reinforcement that contributes to compulsive drug-seeking behavior and addiction (Figure 6).
An overall conceptual theme argued here is that drug addiction represents a break with homeostatic brain regulatory mechanisms that regulate the emotional state of the animal. The dysregulation of emotion begins with the binge and subsequent acute withdrawal, but leaves a residual neuroadaptive trace that allows rapid “re-addiction” even months and years after detoxification and abstinence. Thus, the emotional dysregulation of drug addiction represents more than simply a homeostatic dysregulation of hedonic function; it also represents a dynamic break with homeostasis of this system that has been termed allostasis.
Allostasis, originally conceptualized to explain persistent morbidity of arousal and autonomic function, is defined as “stability through change.” Allostasis is far more complex than homeostasis and has several unique characteristics (Sterling and Eyer, 1988). Allostasis involves a feed-forward mechanism rather than the negative feedback mechanisms of homeostasis, with continuous re-evaluation of need and continuous readjustment of all parameters toward new set points. An allostatic state can be defined as a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level. Allostatic load was defined as the “long-term cost of allostasis that accumulates over time and reflects the accumulation of damage that can lead to pathological states” (McEwen, 2000).
Allostatic mechanisms have been hypothesized to be involved in maintaining a functioning brain reward system that has relevance for the pathology of addiction (Koob and Le Moal, 2001). Two components are hypothesized to adjust to challenges to the brain produced by drugs of abuse: overactivation of brain reward transmitters and circuits and recruitment of the brain anti-reward or brain stress systems. Thus, the very physiological mechanism that allows rapid responses to environmental challenge becomes the source of pathology if adequate time or resources are not available to shut off the response (e.g., the interaction between CRF and norepinephrine in the brainstem and basal forebrain that could lead to pathological anxiety) (Koob, 1999).
Repeated challenges, such as with drugs of abuse, lead to attempts of the brain via molecular, cellular, and neurocircuitry changes to maintain stability but at a cost. For the drug addiction framework elaborated here, the residual deviation from normal brain reward threshold regulation is termed an allostatic state. This state represents a combination of chronic elevation of reward set point fueled by decreased function of reward circuits and recruitment of anti-reward systems, both of which lead to the compulsivity of drug-seeking and drug-taking. How these systems are modulated by other known brain emotional systems localized to the basal forebrain, where the ventral striatum and extended amygdala project to convey emotional valence, how the dysregulation of brain emotional systems impact on the cognitive domain linked to impairments in executive function, and how individuals differ at the molecular-genetic level of analysis to convey loading on these circuits remain challenges for future research.
The author would like to thank Michael Arends and Mellany Santos for their outstanding assistance with the preparation of this manuscript. Research was supported by National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA10072, DA04043, and DA04398 from the National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research also was supported by the Pearson Center for Alcoholism and Addiction Research. This is publication number 19480 from The Scripps Research Institute.
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