Unbalanced Neuronal Circuits in Addiction (2013)

Curr Opin Neurobiol. Author manuscript; available in PMC Aug 1, 2014.

PMCID: PMC3717294


The publisher’s final edited version of this article is available at Curr Opin Neurobiol

See other articles in PMC that cite the published article.

Go to:


Through sequential waves of drug-induced neurochemical stimulation, addiction co-opts the brain’s neuronal circuits that mediate reward, motivation, to behavioral inflexibility and a severe disruption of self-control and compulsive drug intake. Brain imaging technologies have allowed neuroscientists to map out the neural landscape of addiction in the human brain and to understand how drugs modify it.

Systems of circuits

Several theories have been put forward to explain the phenomenon of addiction. For example, unchecked impulsivity [1] (a failure to inhibit excessive drive), reward deficiency [2] (a blunted dopaminergic response to natural rewards), maladaptive learning [3] (the growing incentive salience of a drug’s predictive cues with chronic use), the emergence of opponent processes [4] (the power of negative motivational states underlying withdrawal), faulty decision making [5] (inaccurate computation in preparation for action) or automaticity of responses [6] (inflexibility of stimulus-response habits), have all been the focus of intense and productive research. The fact is that that dysfunctions in these and many other functional modules [5] are likely to contribute, directly or indirectly, to an addicted individual’s inability to suppress a maladaptive behavior in spite of its adverse consequences. The evidence suggests that the observable behaviors that characterize the addiction phenotype (compulsive drug consumption, impaired self-control and behavioral inflexibility) represent unbalanced interactions between complex networks (that form functional circuits) implicated in goal directed behaviors (Figure 1).

An external file that holds a picture, illustration, etc. Object name is nihms449224f1.jpg

A carefully balance set of interconnected functional modules instantiates the processing of myriad and competing signals, including reward, expectation, saliency, motivation, value learning, emotional value, ambiguity, conflict, and cognitive processing that underlie decision making and ultimately our ability to exert free will. Many extrinsic and intrinsic factors (triggers), acting upon a variety of intermediary systems (mediators), can perturb the balance among the system of circuits in charge of orchestrating adaptive goal directed behaviors.

Several external perturbagens (e.g., drugs, food, gambling, sex, video games, high calorie foods, stress) can tip this balance (in vulnerable individuals) and trigger and addictive behavior. At the same time specific neural nodes and their associated networks, when dysfunctional (secondary to genetic or developmental deficits or from drug or other environmental exposures) can destabilize the interaction between brain circuits increasing the vulnerability for psychiatric disorders, including addiction. The molecular mechanisms that result in the improper communication between neuronal networks include changes in NMDA and AMPA receptor-mediated glutamate signaling [7], which will not be discussed here but have been reviewed elsewhere [8•]. The neural nodes, relays and connectivity patterns summarized in the following sections illustrate our current (and growing) understanding of the circuitry underlying addiction.

The Mesostriatocortical System

The ability to form habits has been a powerful and positive force in evolution. Compulsive behaviors, like addiction, can take hold when the neural circuitry that instantiates adaptive habits [9] is thrown off balance by exposure to drugs or other positive (food, sex, gambling) or negative reinforcers (stress) in vulnerable individuals [10]. The ability of certain behavioral routines to become deeply ingrained, after enough repetition, helps explain both the difficulty of suppressing them (i.e., compulsion [1113]) and the ease with which they bounce back after extinction (i.e., relapse [14]). Habituation appears to be instantiated mainly in the mesostriatocortical circuits that ”re-code” the behavioral fate of repetitive actions [14,15] in a process that was aptly referred to as the “chunking” of action repertoires [16••]. Schematic diagrams -at the anatomical and circuit levels- of the main frontocorticostriatal pathways that contribute to reward-related habituation are presented (Figure 2A and B). Drug-induced adaptations anywhere along this bidirectional circuitry, between the ventral tegmental area (VTA) and the neighboring substantia nigra (SN), ventral and dorsal striatum, thalamus, amygdala, hippocampus, subthalamic nucleus and the prefrontal cortex (PFC) can trigger or facilitate the addictive process by disrupting reward-based learning via the modulation of regional neuronal excitability [17,18]. At the molecular level, such adaptations are the reflection of plastic changes that predominantly affect the way in which DA and glutamate neurotransmission become integrated, allowing for synapses to be strengthened or weakened as a result of interneuronal communication [19].

 An external file that holds a picture, illustration, etc. Object name is nihms449224f2.jpg  

Fronto-striatal circuitry of stimulus-response habits. A. Schematic anatomical representation of the mesocorticolimbic dopamine system in the human brain, highlighting several key processing stations: Ventral Tegmental Area (VTA) and Substantia Nigra (SN), Nucleus Accumbens (NAc) in the ventral striatum, Thalamus and Subthalamic Nuclei, and Prefrontal cortex, among others. Modified with permission [15]. B. Four of the frontostriatal cortical circuits that appear to play major roles in executive functioning and inhibitory control. DL: dorsolateral; DM: dorsomedial; VA: ventroanterior; VM: ventromedial; r: right; IFG: inferior frontal gyrus; preSMA: pre somatic motor area; STN: sub-thalamic nucleus. Modified with permission [28].

The DA system is a central cog in the mechanism that attributes saliency, hence its modulatory role in reward and reward prediction (expectation, conditioned learning, motivation (drive), emotional reactivity and executive functions. Many studies have established that DA signals emanating from the VTA/SN and arriving in the striatum play a pivotal role in learning from past experience and orchestrating appropriate behavioral responses. Whether directly or indirectly, all addictive drugs have the power to cause large and transient increases in DA from VTA neurons that project primarily into the Nucleus Accumbens (NAc) of the ventral striatum, but also to the dorsal striatum, amygdala, hippocampus and PFC [20] (Figure 2). Although not yet fully understood, we have made significant progress investigating the underlying processes.

A good example, at the molecular level, is the observation that the two principal classes of medium spiny neurons (MSN) in the striatum differ significantly in terms of their DA receptor patterns of expression: MSNs in the striatonigral (direct) pathway express D1 receptors (D1R), which drive enhanced dendritic excitability and glutamatergic signaling, whereas MSNs in the striatopallidal (indirect) pathway express D2 type receptors (D2R), which appear to mediate the opposite effect [21•]. These differences impact the neurotransmission patterns that influence reward-processing behaviors on the basis of whether or not an expected reward had actually been obtained (Figure 3). For drug reward, studies have shown that an imbalance between D1R (drug-dependently enhanced) and D2R (drug-dependently decreased) signaling facilitates compulsive drug intake [22,23]. For example, administration of antagonists that specifically block either the direct (D1; SCH23390) or indirect (D2; Sulpiride) pathways in the dorsomedial striatum have opposite effects on a task that measures behavioral inhibition, with the former decreasing Stop Signal Reaction Time but having little effect on the Go response, and the latter increasing both Stop Signal Reaction and Go Trial Reaction times [24]. These results suggest that the differential expression of DA receptors in the dorsomedial striatum enables a balanced behavioral inhibition independently of behavioral activation. Interestingly, D1R have low affinity for DA and hence they are active when exposed to large DA increases as occurring during intoxication whereas D2R are high affinity and hence stimulated not just by sharp DA increases but also by the relatively lower levels conveyed by tonic DA levels. Thus, effects of drugs are likely to have shorter duration of action in D1R mediated signaling than in D2R signaling, which was recently corroborated for cocaine’s effects in striatal’s MSN [23]. Stimulation of D1R is necessary for conditioning including that triggered by drugs [25]. The effects of repeated drug exposure in animal models implicate sensitization of D1R signaling whereas both preclinical and clinical studies document decreases in D2R signaling [26,27]. This leads to what appears to be an imbalance between the stimulatory direct D1R mediated striatocortical pathway and the inhibitory D2R mediated indirect pathway. A third, so called hyperdirect pathway, has also been described (also depicted in Figure 2B), in which excitatory projections between the inferior frontal gyrus (IFG) and the subthalamic nuclei (from motor related cortical areas into the globus pallidus) cause thalamic inhibition at a faster speed relative to the direct or indirect pathways, and it has been implicated in the ability to suppress a behavior after it has been initiated [28].

An external file that holds a picture, illustration, etc. Object name is nihms449224f3.jpg   

Schematic depiction of dopaminergic control of positive and negative motivation loops in the dorsal striatum. A. When an action results in a better-than-predicted situation, DA neurons fire a burst of spikes, which is likely to activate D1Rs on direct pathway neurons and facilitate immediate action and corticostriatal plasticity changes that make it more likely to select that action in the future. B. In contrast, when the result of an action is worse-than-expected, DA neurons are inhibited reducing DA, which is likely to inhibit D2Rs indirect pathway neurons, suppressing immediate action and the reinforcement of corticostriatal synapses, leading to suppression of that action in the future. Reprinted with permission [101].

A better understanding of the biological and environmental forces that shape the mesostriatocortical circuits is bound to translate into more effective interventions. For example, maternal stress has been shown to negatively affect the dendritic arborization in the NAc and in prefrontocortical structures of the developing fetus [29•]. Similarly children reared in orphanages show underdeveloped frontal connectivity [30••]. Because of the central position of the NAc in the circuit that translates motivational inputs from the limbic system into goal-directed behaviors, and its connectivity with the PFC, which is necessary for self-control, these findings could help explain the association between early adverse events, brain development trajectories, and mental health [3133].

Similarly, our better understanding of mesostriatocortical circuits has also started to shed light into the neurobiological processed that underlie the inverse relationship between age of initial drug use and addiction risk [34]. For example, the change from a predominant influence of the SN as the source of DA connectivity to subcortical and cortical regions in childhood/adolescence to a combined influence of the SN and the VTA in young adulthood [35•] could make this transition period particularly sensitive to the increased vulnerability to substance use and other psychiatric disorders, observed early in life. The discovery of this maturational effect suggests important new research questions. For example, could this connectivity shift modulate the regulatory impact of the corticotropin releasing factor binding protein (CRF-BP), a modulatory factor that can potentiate glutamatergic responses [36] implicated in reinstatement of cocaine seeking [37], and that is expressed in VTA but not in SN [38]?

Limbic Hubs

The core mesostriatocortical circuitry outlined above interacts with other structures in the limbic system that influence reward-related behaviors by providing information related to, among others, emotional valence, stored memories, sexual and endocrine function, autonomic control, interoception, and energy homeostasis. Below, we highlight key recent finding pertaining to the involvement of some of these nodes in substance use disorders (SUDs).


The amygdala encodes loss aversion and injects emotion and fear in the decision-making process. It also appears to act in concert with the ventral striatum to pick up stimuli that are not just emotionally salient but highly relevant to a task-dependent reward [39]. The extended amygdala (central nucleus of the amygdala, bed nucleus of the stria terminalis, and NAc shell), through increased signaling via the corticotropin-releasing factor (CRF) and CRF-related peptides, is also involved in stress responses and contributes (but see also the case for the habenula, below) to a broader anti-reward system [40••]. The amygdala is a powerful modulator of addictive behaviors, especially during the protracted incubation of cue-induced drug cravings [41]. The basolateral amygdala (BLA) receives dopaminergic innervations from the VTA and expresses D1 and D2 receptors, which differentially influence the modulation of NAc and PFC function by the BLA. For example, intra-BLA administration of a D1R antagonist potentiates stress-induced DA release in NAc while attenuating it in medial PFC (mPFC) whereas a D2R antagonist had no effect on these regions [42]. It should be added that D3 type receptors in the central amygdala also play a role in the incubation of cocaine craving [43••]. Not surprisingly, there is some evidence to suggest that deep brain stimulation of the amygdala could help in the treatment of various mental disorders, including addiction [44•].


The transition from flexible, goal directed to reflexive, compulsive behaviors appears to also be influenced by instrumental learning as modulated by interoceptive and exteroceptive inputs. The insula plays a major interoceptive role by sensing and integrating information about the internal physiological state (in the context of ongoing activity) and conveying it to the anterior cingulate cortex (ACC), ventral striatum (VS), and ventral medial PFC (vmPFC) to initiate adaptive behaviors [45]. Consistent with its role in bridging changes in internal state and cognitive and affective processing, neuroimaging studies have revealed that the middle insula plays a critical role in cravings for food, cocaine and cigarettes [4648] and on how an individual handles drug withdrawal symptoms. Thus, insular dysfunction is associated with drug craving in addiction [49], a notion that is supported by the documented ease with which smokers who had suffered insular damage were able to quit [50••], as well as by several imaging studies of addicted individuals [51,52]. The observed associations between alcohol and insular hypofunction [53], and between heroin and cocaine use and gray insular matter deficits relative to controls [54], may also account for the deficits in self-awareness during intoxication and the failure to recognize the pathological state of addiction by the addicted individual, which has been traditionally ascribed to denial [55]. [55]. In fact, many imaging studies show differential activation of the insula during craving [56], which has been suggested to serve as a biomarker to predict relapse [57].

Thalamus, subthalamic nucleus (STN), epithalamus

Chronic drug abuse eventually impinges on the connectivity of critical hubs [58]. For example, cocaine abusers, compared to controls, present lower functional connectivity between midbrain (location of SN and VTA) and thalamus, cerebellum, and rostral ACC, which is associated with reduced activation in thalamus and cerebellum and enhanced deactivation in rostral ACC [59]. The performance of these hubs, and their multiple targets, can be perturbed not just by chronic but also by acute exposure to drugs of abuse: for example, alcohol intoxication can cause a fuel switch, from glucose to acetate, in the thalamus, cerebellum and occipital cortex and this switch is facilitated with chronic alcohol exposures [60•]. On the other hand, a recent study of 15 treatment-seeking cocaine-addicted individuals found that just 6 months of abstinence could rescue much of the reduced neural activity in midbrain (encompassing VTA/SN) and thalamus (encompassing the mediodorsal nucleus), which reduced cocaine seeking behavior as simulated in a drug word choice task [61••].

The STN plays a vital role in the integration of limbic and associative information in preparation for its transmission towards cortical and subcortical regions [62]. It regulates motor action and is involved in decision making particularly when engaging in difficult choice decisions [63,64]. Several studies have implicated the STN in addiction. One report, for example, found that the robust crosstalk between impulse control and cognitive processing that improves substance use outcomes and contributes to adolescent resiliency hinges heavily on STN performance [65]. Deep brain stimulation of the STN, which is used in the treatment of Parkinson’s [66] and might be useful in severe OCD [67] has been tested in preclinical studies to reduce the sensitized responses to cocaine-cues [68].

DA signaling from VTA and SN is critical for learning approach behaviors from reward whereas inhibition of VTA DA signaling by the lateral habenula enables learning avoiding behaviors when an expected reward does not materialize [69] or when an aversive stimulus or negative feedback is provided [70]. Thus, the lateral habenula together with amygdala/stress system may constitute part of an anti-reward circuitry in the brain that negatively motivates behaviors. This is consistent with the results of a preclinical study in which activation of the lateral habenula triggered relapse to cocaine and heroin self-administration [71,72]. Current thinking then posits that chronic use of addictive drugs leads to habenular hyperactivity, which promotes a negative emotional state during drug withdrawal [73].


Convergent studies are also implicating the cerebellum, and the cerebellar vermis in particular, in addiction. For example, the cerebellum, along with the occipital cortex and thalamus is one of the brain areas that undergoes the steepest activation in response to intravenous methylphenidate [74••] and, like in the thalamus, the effect in the vermis was significantly amplified (~50%) whenever methylphenidate was expected by cocaine abusers, suggesting its involvement in expectation of drug reinforcement [74••]. Indeed, other studies have found that cocaine cues can trigger the activation of cerebellar vermis in cocaine users [75], and that vermis activation was associated with abstinence in alcohol addiction [76]. A likely contribution of the cerebellum to the addiction process is also suggested by imaging studies implicating it in cognitive processes underlying the execution of goal-directed behaviors and their inhibition when they are perceived as disadvantageous [75•].

The dopamine content in cerebellum is low so it had not been traditionally considered as part of the circuitry modulated by DA [77]. However, the primate cerebellar vermis (lobules II–III and VIII–IX) displays significant axonal dopamine transporter immunoreactivity, which, together with the existence of VTA projections to the cerebellum suggests that a reciprocal midbrain to cerebellum circuit is likely [78]. The relevance of VTA-cerebellar vermis communication to reward processing is also supported by independent human fMRI based observations of correlated neural activity in VTA and cerebellar vermis while viewing faces of the opposite sex [79] and of strong functional connectivity between VTA and SV and the cerebellar vermis (Tomasi and Volkow, in press).

Frontocortical Substrates

Much of early addiction research focused on limbic brain areas because of their role in drug reward [80]. However, the drug-induced DA boost, does not explain addiction since it happens in naïve animals and its magnitude is decreased in addiction [81•]. In contrast, preclinical and clinical studies are revealing neuroadaptations in PFC that are uniquely activated by the drug or drug cues in addicted but not in non-addicted individuals and are therefore likely to play a key role in the addiction phenotype (for review, see [82]).

In humans addicted to drugs, the reduction in striatal D2R, which is implicated in some impulsive and compulsive behavioral phenotypes [83], is associated with decreased activity of PFC regions, including orbitofrontal cortex (OFC), ACC, and dorsolateral prefrontal cortex (DLPFC) [8486]. Studies have also shown, decreased frontal cortical activity during intoxication for many of the drugs of abuse [87] that remains after drug discontinuation in chronic abusers [88]. Indeed, disruption of several frontocortical processes has been reported in chronic drug users (Table I) (see [13] for a review). Naturally, targeting the frontal impairments in addiction has been a holy grail of therapeutic strategies to improve self-control [61] [89].

Table 1      

Processes associated with the prefrontal cortex that are disrupted in addiction

Among the frontal regions implicated in addiction the OFC, ACC, DLPFC and inferior frontal gyrus (IFG; Brodmann area 44) stand out because of their participation in salience attribution, inhibitory control/emotion regulation, decision making and behavioral inhibition respectively (Figure 2B). It has been postulated that their improper regulation by D2R-mediated striatal DA signaling in addicted subjects could underlie the enhanced motivational value of drugs and the loss of control over drug intake [90••]. Incidentally, related dysfunctions could also underlie some behavioral addictions, like pathological internet use [91] and compulsive food intake in some forms of obesity [83]. Interestingly, and echoing a recurring theme, investigators have also found evidence of differential roles for D1R and D2R in the PFC. For example, recent preclinical studies have shown that pharmacologic blockade of mPFC D1R attenuates; whereas D2R increases a tendency for risky choices, providing evidence for a dissociable but complementary role of mPFC DA receptors that is likely to play a major role in orchestrating the fine balance needed for inhibitory control, delayed discounting, and judgment [92].

In addition, because impairments in OFC and ACC are associated with compulsive behaviors and impulsivity, DA’s impaired modulation of these regions is likely to contribute to the compulsive and impulsive drug intake seen in addiction [93]. Clearly, low DA tone could just as well constitute a preexisting vulnerability for drug use in PFC, albeit one that is likely to be exacerbated with the further decreases in striatal D2R triggered by repeated drug use. Indeed, a study performed in subjects who, despite a positive family history (high risk) of alcoholism, were not themselves alcoholics, revealed a higher than normal striatal D2R availability that was associated with normal metabolism in OFC, ACC, and DLPFC [94•]. This suggests that, in these subjects at risk for alcoholism, the normal PFC function was linked to enhanced striatal D2R signaling, which in turn may have protected them from alcohol abuse.

Also suggestive of compensatory mechanisms that could afford protection to some members of an at-risk family, a recent study of siblings discordant for their addiction to stimulant drugs [95••] showed brain differences in the morphology of their OFC, which were significantly smaller in the addicted sibling than in controls, whereas in the non-addicted siblings the OFC did not differ from that of controls [96].

Treatment implications

Increasing our understanding of the neural systems affected by chronic drug use as well as the modulatory impact that genes in conjunction with developmental and environmental forces have on these neuronal processes, will improve our ability to design more effective strategies for prevention and treatment of SUD.

Irrespective of whether or which of the addiction-related impairments highlighted in this review lead to or follow chronic drug use, the combined multidisciplinary evidence suggests the existence of multiple neuronal circuits that become dysfunctional with addiction and that could be targeted more precisely through pharmacological, physical, or behavioral means to attempt and mitigate, halt, or even reverse a specific deficit. For example, functional MRI studies show that oral methylphenidate can normalize activity in two major ACC subdivisions (i.e., the caudal-dorsal and the rostroventromedial) and decrease impulsivity in cocaine addicted individuals during an emotionally salient cognitive task [97•]. Similarly, a better understanding of the main nodes within circuits disrupted by addiction offers potential targets for investigating the value of transcranial magnetic stimulation (TMS) or even deep brain stimulation (DBS) in treatment-refractory patients suffering from addiction [98•]. Finally, evidence-based psychosocial interventions are becoming more effective and available for the treatment of SUDs, a trend that is likely to accelerate thanks to the development and deployment of novel approaches enhanced by digital, virtual, and mobile technologies [99], and by our expanded understanding of the social brain, which will allow us to take advantage of the powerful influence of social factors in modulating neuronal circuits and human behaviors [100].


  • Addiction is a spectrum disorder that perturbs the balance within a network of circuits.
  • Addiction entails a progressive dysfunction that erodes the foundations of self-control.
  • Addiction circuits overlap with the circuits of other impulsivity disorders (e.g., obesity).
  • Better understanding of these circuits is the key to better prevention and treatment.


Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Bechara A. Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective. Nat Neurosci. 2005;8:1458–1463. [PubMed]
2. Blum K, Gardner E, Oscar-Berman M, Gold M. “Liking” and “wanting” linked to Reward Deficiency Syndrome (RDS): hypothesizing differential responsivity in brain reward circuitry. Curr Pharm Des. 2012;18:113–118. [PMC free article] [PubMed]
3. Berridge KC. The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology (Berl) 2007;191:391–431. [PubMed]
4. 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]
5. Redish AD, Jensen S, Johnson A. A unified framework for addiction: vulnerabilities in the decision process. Behav Brain Sci. 2008;31:415–437. discussion 437–487. [PMC free article] [PubMed]
6. Belin D, Jonkman S, Dickinson A, Robbins TW, Everitt BJ. Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behav Brain Res. 2009;199:89–102. [PubMed]
7. Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162:1403–1413. [PubMed]
8. Moussawi K, Kalivas PW. Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction. Eur J Pharmacol. 2010;639:115–122. [PubMed] •Excellent introductory review to the drug-induced deficits in glutamatergic signaling throughout the mesocorticolimbic structures and the complex mechanisms whereby mGlu2/3 receptors can modulate both reward processing and drug seeking.
9. Sesack SR, Grace AA. Cortico-Basal Ganglia reward network: microcircuitry. Neuropsychopharmacology. 2010;35:27–47. [PMC free article] [PubMed]
10. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci. 2005;8:1481–1489. [PubMed]
11. Choi JS, Shin YC, Jung WH, Jang JH, Kang DH, Choi CH, Choi SW, Lee JY, Hwang JY, Kwon JS. Altered Brain Activity during Reward Anticipation in Pathological Gambling and Obsessive-Compulsive Disorder. PLoS One. 2012;7:e45938. [PMC free article] [PubMed]
12. Filbey FM, Myers US, Dewitt S. Reward circuit function in high BMI individuals with compulsive overeating: Similarities with addiction. Neuroimage. 2012;63:1800–1806. [PubMed]
13. Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci. 2012;12:652–669. [PMC free article] [PubMed]
14. Barnes TD, Kubota Y, Hu D, Jin DZ, Graybiel AM. Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories. Nature. 2005;437:1158–1161. [PubMed]
15. Graybiel AM. Habits, rituals, and the evaluative brain. Annu Rev Neurosci. 2008;31:359–387. [PubMed]
16. Graybiel AM. The basal ganglia and chunking of action repertoires. Neurobiol Learn Mem. 1998;70:119–136. [PubMed] ••Critical review that presents a cogent model of how the basal ganglia can recode repeated behaviors so that they can be implemented as performance units.
17. Girault JA. Integrating neurotransmission in striatal medium spiny neurons. Adv Exp Med Biol. 2012;970:407–429. [PubMed]
18. Shiflett MW, Balleine BW. Molecular substrates of action control in cortico-striatal circuits. Prog Neurobiol. 2011;95:1–13. [PMC free article] [PubMed]
19. Rodriguez Parkitna J, Engblom D. Addictive drugs and plasticity of glutamatergic synapses on dopaminergic neurons: what have we learned from genetic mouse models? Front Mol Neurosci. 2012;5:89. [PMC free article] [PubMed]
20. Morales M, Pickel VM. Insights to drug addiction derived from ultrastructural views of the mesocorticolimbic system. Ann N Y Acad Sci. 2012;1248:71–88. [PubMed]
21. Surmeier DJ, Ding J, Day M, Wang Z, Shen W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 2007;30:228–235. [PubMed] •Understanding how dopamine signaling can accomplish such a wide array of behavioral tasks has proven to be an enormous challenge. This article illustrates the power of genetic and neurophysiological studies to dissect the subtle differences at the molecular and cellular levels underlying the versatile nature of synaptic plasticity in the striatum.
22. Berglind WJ, Case JM, Parker MP, Fuchs RA, See RE. Dopamine D1 or D2 receptor antagonism within the basolateral amygdala differentially alters the acquisition of cocaine-cue associations necessary for cue-induced reinstatement of cocaine-seeking. Neuroscience. 2006;137:699–706. [PubMed]
23. Luo Z, Volkow ND, Heintz N, Pan Y, Du C. Acute cocaine induces fast activation of D1 receptor and progressive deactivation of D2 receptor striatal neurons: in vivo optical microprobe [Ca2+]i imaging. J Neurosci. 2011;31:13180–13190. [PMC free article] [PubMed]
24. Eagle DM, Wong JC, Allan ME, Mar AC, Theobald DE, Robbins TW. Contrasting roles for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats. J Neurosci. 2011;31:7349–7356. [PMC free article] [PubMed]
25. Parker JG, Zweifel LS, Clark JJ, Evans SB, Phillips PE, Palmiter RD. Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning. Proc Natl Acad Sci U S A. 2010;107:13491–13496. [PMC free article] [PubMed]
26. Thompson D, Martini L, Whistler JL. Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine. PLoS One. 2010;5:e11038. [PMC free article] [PubMed]
27. Volkow ND, Fowler JS, Wolf AP, Schlyer D, Shiue CY, Alpert R, Dewey SL, Logan J, Bendriem B, Christman D, et al. Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry. 1990;147:719–724. [PubMed]
28. Feil J, Sheppard D, Fitzgerald PB, Yucel M, Lubman DI, Bradshaw JL. Addiction, compulsive drug seeking, and the role of frontostriatal mechanisms in regulating inhibitory control. Neurosci Biobehav Rev. 2010;35:248–275. [PubMed]
29. Muhammad A, Carroll C, Kolb B. Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex. Neuroscience. 2012;216:103–109. [PubMed] •It is known that stress during development can have devastating consequences on later mental health, yet little is known about the mechanisms involved. By looking at the effects of prenatal/developmental stress in rodents, this study uncovered significant stress-induced changes in axon morphology (e.g., dendritic branching, length, spine density) within key nodes along the mesocorticostriatal axis.
30. Eluvathingal TJ, Chugani HT, Behen ME, Juhasz C, Muzik O, Maqbool M, Chugani DC, Makki M. Abnormal brain connectivity in children after early severe socioemotional deprivation: a diffusion tensor imaging study. Pediatrics. 2006;117:2093–2100. [PubMed] ••Using a non-invasive brain imaging technique, this study uncovered region-specific decreases in fractional anisotropy (a marker of white matter health) in children with a history of early severe socioemotional deprivation recruited from Eastern European orphanages. Importantly, the deficits help explain the previously observed mild specific cognitive impairment and impulsivity in these children.
31. Laplante DP, Brunet A, Schmitz N, Ciampi A, King S. Project Ice Storm: prenatal maternal stress affects cognitive and linguistic functioning in 5 1/2-year-old children. J Am Acad Child Adolesc Psychiatry. 2008;47:1063–1072. [PubMed]
32. Bennett DS, Bendersky M, Lewis M. Children’s cognitive ability from 4 to 9 years old as a function of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence. Dev Psychol. 2008;44:919–928. [PMC free article] [PubMed]
33. Rosenberg SD, Lu W, Mueser KT, Jankowski MK, Cournos F. Correlates of adverse childhood events among adults with schizophrenia spectrum disorders. Psychiatr Serv. 2007;58:245–253. [PubMed]
34. Stinson FS, Ruan WJ, Pickering R, Grant BF. Cannabis use disorders in the USA: prevalence, correlates and co-morbidity. Psychol Med. 2006;36:1447–1460. [PubMed]
35. Tomasi D, Volkow N. Functional connectivity of substantia nigra and ventral tegmental area: maturation during adolescence and effects of ADHD. Cerebral Cortex. 2012 in press. [PubMed] •This imaging study of brain maturation has uncovered important information that could help explain why addiction is a developmental disease. The findings exposed a critical and protracted process during which the source of dopaminergic innervations into cortical and subcortical areas shifts, from a preponderance of SN input during childhood/adolescence to a combined SN/VTA origin during young adulthood.
36. Ungless MA, Singh V, Crowder TL, Yaka R, Ron D, Bonci A. Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons. Neuron. 2003;39:401–407. [PubMed]
37. Wise RA, Morales M. A ventral tegmental CRF-glutamate-dopamine interaction in addiction. Brain Res. 2010;1314:38–43. [PMC free article] [PubMed]
38. Wang HL, Morales M. Corticotropin-releasing factor binding protein within the ventral tegmental area is expressed in a subset of dopaminergic neurons. J Comp Neurol. 2008;509:302–318. [PMC free article] [PubMed]
39. Ousdal OT, Reckless GE, Server A, Andreassen OA, Jensen J. Effect of relevance on amygdala activation and association with the ventral striatum. Neuroimage. 2012;62:95–101. [PubMed]
40. Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci. 2005;8:1442–1444. [PubMed] ••Addiction is not only the manifestation of craving euphoria. As this review beautifully illustrates, chronic drug abuse eventually recruits anti-reward systems (e.g., amygdala, habenula) that greatly contribute to the cycle of unfulfilled desire underlying addictive behaviors.
41. Pickens CL, Airavaara M, Theberge F, Fanous S, Hope BT, Shaham Y. Neurobiology of the incubation of drug craving. Trends Neurosci. 2011;34:411–420. [PMC free article] [PubMed]
42. Stevenson CW, Gratton A. Basolateral amygdala modulation of the nucleus accumbens dopamine response to stress: role of the medial prefrontal cortex. Eur J Neurosci. 2003;17:1287–1295. [PubMed]
43. Xi ZX, Li X, Li J, Peng XQ, Song R, Gaal J, Gardner EL. Blockade of dopamine D(3) receptors in the nucleus accumbens and central amygdala inhibits incubation of cocaine craving in rats. Addict Biol. 2012 [PMC free article] [PubMed] ••Dopamine receptors type 2 and 3 have long been the target of much focused research in drug abuse and addiction. But, as this article shows, there is an increasing realization that Type 3 Dopamine receptors also play important roles, at the very least in the incubation process underlying drug cravings. Thus, D3R have emerged as promising target for the development of new addiction pharmacotherapies.
44. Langevin JP. The amygdala as a target for behavior surgery. Surg Neurol Int. 2012;3:S40–S46. [PubMed] •This review offers an updated view of the potential therapeutic role for deep brain stimulation of the amygdala (a mesiotemporal structure long considered the primary site of fear and anger) in the treatment of anxiety disorders, addiction, and mood disorders.
45. Paulus MP, Tapert SF, Schulteis G. The role of interoception and alliesthesia in addiction. Pharmacol Biochem Behav. 2009;94:1–7. [PMC free article] [PubMed]
46. Bonson KR, Grant SJ, Contoreggi CS, Links JM, Metcalfe J, Weyl HL, Kurian V, Ernst M, London ED. Neural systems and cue-induced cocaine craving. Neuropsychopharmacology. 2002;26:376–386. [PubMed]
47. Pelchat ML, Johnson A, Chan R, Valdez J, Ragland JD. Images of desire: food-craving activation during fMRI. Neuroimage. 2004;23:1486–1493. [PubMed]
48. Wang Z, Faith M, Patterson F, Tang K, Kerrin K, Wileyto EP, Detre JA, Lerman C. Neural substrates of abstinence-induced cigarette cravings in chronic smokers. J Neurosci. 2007;27:14035–14040. [PMC free article] [PubMed]
49. Verdejo-Garcia A, Clark L, Dunn BD. The role of interoception in addiction: A critical review. Neurosci Biobehav Rev. 2012;36:1857–1869. [PubMed]
50. Naqvi NH, Rudrauf D, Damasio H, Bechara A. Damage to the insula disrupts addiction to cigarette smoking. Science. 2007;315:531–534. [PubMed] ••A seminal study that showed for the first time that damage to the insular cortex (in stroke patients) can lead to an abrupt disruption of the desire to smoke, suggesting how bodily signals contribute to addiction.
51. Kang OS, Chang DS, Jahng GH, Kim SY, Kim H, Kim JW, Chung SY, Yang SI, Park HJ, Lee H, et al. Individual differences in smoking-related cue reactivity in smokers: an eye-tracking and fMRI study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:285–293. [PubMed]
52. Goudriaan AE, de Ruiter MB, van den Brink W, Oosterlaan J, Veltman DJ. Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study. Addict Biol. 2010;15:491–503. [PMC free article] [PubMed]
53. Padula CB, Simmons AN, Matthews SC, Robinson SK, Tapert SF, Schuckit MA, Paulus MP. Alcohol attenuates activation in the bilateral anterior insula during an emotional processing task: a pilot study. Alcohol Alcohol. 2011;46:547–552. [PMC free article] [PubMed]
54. Gardini S, Venneri A. Reduced grey matter in the posterior insula as a structural vulnerability or diathesis to addiction. Brain Res Bull. 2012;87:205–211. [PubMed]
55. Goldstein RZ, Craig AD, Bechara A, Garavan H, Childress AR, Paulus MP, Volkow ND. The neurocircuitry of impaired insight in drug addiction. Trends Cogn Sci. 2009;13:372–380. [PMC free article] [PubMed]
56. Naqvi NH, Bechara A. The hidden island of addiction: the insula. Trends Neurosci. 2009;32:56–67. [PMC free article] [PubMed]
57. Janes AC, Pizzagalli DA, Richardt S, de BFB, Chuzi S, Pachas G, Culhane MA, Holmes AJ, Fava M, Evins AE, et al. Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence. Biol Psychiatry. 2010;67:722–729. [PubMed] ••This study showed that the complex patterns of brain activation in response to smoking-related cues can be used reliably to identify relapse-prone smokers before quit attempts. This study has tremendous translational potential for it could enable personalized treatment and improve tobacco-dependence treatment outcomes
58. Tomasi D, Volkow ND. Association between functional connectivity hubs and brain networks. Cereb Cortex. 2011;21:2003–2013. [PMC free article] [PubMed]
59. Tomasi D, Volkow ND, Wang R, Carrillo JH, Maloney T, Alia-Klein N, Woicik PA, Telang F, Goldstein RZ. Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers. PLoS One. 2010;5:e10815. [PMC free article] [PubMed]
60. Volkow ND, Kim S, Wang GJ, Alexoff D, Logan J, Muench L, Shea C, Telang F, Fowler JS, Wong C, et al. Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain. Neuroimage. 2012 [PMC free article] [PubMed] •According to this imaging study acute alcohol causes the brain to shift fuel usage away from glucose and in favor of acetate. The differential shift observed in various areas of the brain; particularly in the cerebellum provide important new insight related to the adverse effects of alcoholism.
61. Moeller SJ, Tomasi D, Woicik PA, Maloney T, Alia-Klein N, Honorio J, Telang F, Wang GJ, Wang R, Sinha R, et al. Enhanced midbrain response at 6-month follow-up in cocaine addiction, association with reduced drug-related choice. Addict Biol. 2012 [PMC free article] [PubMed] ••One of the most important research questions in addiction relates to how much brain function can be recovered with abstinence, and where the functional recovery takes place. By testing the blood oxygen level dependent (BOLD) response in dopaminergic fields in cocaine addicted individuals 6 months after treatment, this study established that fMRI (combined with behavioral testing) could provide sensitive biomarkers of abstinence-related outcomes in drug addiction.
62. Temel Y, Blokland A, Steinbusch HW, Visser-Vandewalle V. The functional role of the subthalamic nucleus in cognitive and limbic circuits. Prog Neurobiol. 2005;76:393–413. [PubMed]
63. Zaghloul KA, Weidemann CT, Lega BC, Jaggi JL, Baltuch GH, Kahana MJ. Neuronal activity in the human subthalamic nucleus encodes decision conflict during action selection. J Neurosci. 2012;32:2453–2460. [PMC free article] [PubMed]
64. Whitmer D, White C. Evidence of human subthalamic nucleus involvement in decision making. J Neurosci. 2012;32:8753–8755. [PubMed]
65. Weiland BJ, Nigg JT, Welsh RC, Yau WY, Zubieta JK, Zucker RA, Heitzeg MM. Resiliency in Adolescents at High Risk for Substance Abuse: Flexible Adaptation via Subthalamic Nucleus and Linkage to Drinking and Drug Use in Early Adulthood. Alcohol Clin Exp Res. 2012;36:1355–1364. [PMC free article] [PubMed]
66. van Wouwe NC, Ridderinkhof KR, van den Wildenberg WP, Band GP, Abisogun A, Elias WJ, Frysinger R, Wylie SA. Deep brain stimulation of the subthalamic nucleus improves reward-based decision-learning in Parkinson’s disease. Front Hum Neurosci. 2011;5:30. [PMC free article] [PubMed]
67. Chabardes S, Polosan M, Krack P, Bastin J, Krainik A, David O, Bougerol T, Benabid AL. Deep Brain Stimulation for Obsessive-Compulsive Disorder: Subthalamic Nucleus Target. World Neurosurg. 2012 [PubMed]
68. Rouaud T, Lardeux S, Panayotis N, Paleressompoulle D, Cador M, Baunez C. Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation. Proc Natl Acad Sci U S A. 2010;107:1196–1200. [PubMed] •Deep brain stimulation (DBS) represents a reversible way to inactivate a particular structure in the brain. This preclinical study showed that targeting the subthalamic nucleus with DBS did not affect the consummatory processes for either food or cocaine when the behavioral cost to obtain the reward is low. However, STN DBS did decrease the willingness to work (motivation) for a cocaine infusion without affecting the motivation for food.
69. Matsumoto M, Hikosaka O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature. 2007;447:1111–1115. [PubMed]
70. Matsumoto M, Hikosaka O. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci. 2009;12:77–84. [PMC free article] [PubMed]
71. Zhang F, Zhou W, Liu H, Zhu H, Tang S, Lai M, Yang G. Increased c-Fos expression in the medial part of the lateral habenula during cue-evoked heroin-seeking in rats. Neurosci Lett. 2005;386:133–137. [PubMed]
72. Brown RM, Short JL, Lawrence AJ. Identification of brain nuclei implicated in cocaine-primed reinstatement of conditioned place preference: a behaviour dissociable from sensitization. PLoS One. 2011;5:e15889. [PMC free article] [PubMed]
73. Baldwin PR, Alanis R, Salas R. The Role of the Habenula in Nicotine Addiction. J Addict Res Ther. 2011:S1. [PMC free article] [PubMed]
74. Volkow ND, Wang GJ, Ma Y, Fowler JS, Zhu W, Maynard L, Telang F, Vaska P, Ding YS, Wong C, et al. Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J Neurosci. 2003;23:11461–11468. [PubMed] ••A brain imaging study that provides a clear illustration of the power of expectation, by highlighting the dramatically different patterns of brain metabolic activity –and self reports of high and drug liking-, induced whenever the arrival of a stimulant (methylphenidate) was expected (relative to when it was not).
75. Anderson CM, Maas LC, Frederick B, Bendor JT, Spencer TJ, Livni E, Lukas SE, Fischman AJ, Madras BK, Renshaw PF, et al. Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacology. 2006;31:1318–1326. [PubMed] •The cerebellum is not usually considered as a integral part of the reward circuitry, but there is growing evidence that this view will need to be revisited
76. Janu L, Rackova S, Horacek J. Regional cerebellar metabolism (18FDG PET) predicts the clinical outcome of the short-term inpatient treatment of alcohol addiction. Neuro Endocrinol Lett. 2012;33 [PubMed]
77. Kalivas PW, McFarland K. Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl) 2003;168:44–56. [PubMed]
78. Ikai Y, Takada M, Mizuno N. Single neurons in the ventral tegmental area that project to both the cerebral and cerebellar cortical areas by way of axon collaterals. Neuroscience. 1994;61:925–934. [PubMed]
79. Zeki S, Romaya J. The brain reaction to viewing faces of opposite- and same-sex romantic partners. PLoS One. 2010;5:e15802. [PMC free article] [PubMed]
80. Di Chiara G. Drug addiction as dopamine-dependent associative learning disorder. Eur J Pharmacol. 1999;375:13–30. [PubMed]
81. Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Chen AD, Dewey SL, Pappas N. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386:830–833. [PubMed] •Using PET to compare the responses of cocaine addicts and normal controls to intravenous methylphenidate, this study showed that addicts have reduced dopamine release in the striatum and a reduced “high” relative to controls. These findings challenge the notion that addiction involves an enhanced striatal dopamine response to cocaine and/or an enhanced induction of euphoria.
82. Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002;159:1642–1652. [PMC free article] [PubMed]
83. Volkow ND, Wang GJ, Tomasi D, Baler RD. Obesity and addiction: neurobiological overlaps. Obes Rev. 2012 [PubMed]
84. Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey SL, Wolf AP. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse. 1993;14:169–177. [PubMed]
85. Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M, Logan J, Franceschi D, Gatley J, Hitzemann R, et al. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry. 2001;158:2015–2021. [PubMed]
86. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Jayne M, Ma Y, Pradhan K, Wong C. Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci. 2007;27:12700–12706. [PubMed]
87. Chang L, Chronicle EP. Functional imaging studies in cannabis users. Neuroscientist. 2007;13:422–432. [PubMed]
88. Volkow N, Hitzemann R, Wang GJ, Fowler J, Wolf A, Dewey S, Handlesman L. Long-term frontal brain metabolic changes in cocaine abusers. Synapse. 1992;11:184–190. [PubMed]
89. Goldstein RZ, Woicik PA, Maloney T, Tomasi D, Alia-Klein N, Shan J, Honorio J, Samaras D, Wang R, Telang F, et al. Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task. Proc Natl Acad Sci U S A. 2010;107:16667–16672. [PMC free article] [PubMed]
90. Volkow ND, Fowler JS. Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb Cortex. 2000;10:318–325. [PubMed] ••A very influential model, based on imaging data, is presented that posits that pleasure per se is not enough to maintain compulsive drug administration in the drug addicted subject and that the intermittent dopaminergic activation of reward circuits, secondary to chronic drug abuse, may add a critical element by disrupting the orbitofrontal cortex, which becomes hypoactive in proportion to the levels of dopamine D2 receptors in the striatum.
91. Yuan K, Qin W, Wang G, Zeng F, Zhao L, Yang X, Liu P, Liu J, Sun J, von Deneen KM, et al. Microstructure abnormalities in adolescents with internet addiction disorder. PLoS One. 2012;6:e20708. [PMC free article] [PubMed]
92. St Onge JR, Abhari H, Floresco SB. Dissociable contributions by prefrontal D1 and D2 receptors to risk-based decision making. J Neurosci. 2011;31:8625–8633. [PubMed]
93. Volkow N, Fowler J. Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb Cortex. 2000;10:318–325. [PubMed]
94. Volkow ND, Wang GJ, Begleiter H, Porjesz B, Fowler JS, Telang F, Wong C, Ma Y, Logan J, Goldstein R, et al. High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. Arch Gen Psychiatry. 2006;63:999–1008. [PubMed] •Low levels of D2R had been shown to increase vulnerability to stimulant use by modulating the quality of the experience in naïve individuals. This study presents the other side of the same coin, by showing that higher-than-normal D(2) receptor availability in nonalcoholic members of alcoholic families supports the hypothesis that high levels of D(2) receptors may protect against alcoholism.
95. Ersche KD, Jones PS, Williams GB, Turton AJ, Robbins TW, Bullmore ET. Abnormal brain structure implicated in stimulant drug addiction. Science. 2012;335:601–604. [PubMed] ••This study identified abnormalities in the connectivity between drive and control circuits in the brain that are associated with poorer behavioral control of prepotent responses not only in addicted individuals but also in their nonaddicted siblings as compared to a control group of unrelated healthy individuals
96. Parvaz MA, Maloney T, Moeller SJ, Woicik PA, Alia-Klein N, Telang F, Wang GJ, Squires NK, Volkow ND, Goldstein RZ. Sensitivity to monetary reward is most severely compromised in recently abstaining cocaine addicted individuals: A cross-sectional ERP study. Psychiatry Res. 2012 [PMC free article] [PubMed]
97. Goldstein RZ, Volkow ND. Oral methylphenidate normalizes cingulate activity and decreases impulsivity in cocaine addiction during an emotionally salient cognitive task. Neuropsychopharmacology. 2011;36:366–367. [PubMed] •This fMRI study was the first to show that oral methylphenidate (MPH) improved the response of the anterior cingulate cortex and associated task performance in cocaine addicted individuals, consistent with the cognitive benefits of MPH in other psychopathologies.
98. Luigjes J, van den Brink W, Feenstra M, van den Munckhof P, Schuurman PR, Schippers R, Mazaheri A, De Vries TJ, Denys D. Deep brain stimulation in addiction: a review of potential brain targets. Mol Psychiatry. 2011;17:572–583. [PubMed] •An updated review of preclinical and clinical studies highlighting the potential targets and benefits for using DBS for the treatment of substance use disorders.
99. Marsch LA, Dallery J. Advances in the psychosocial treatment of addiction: the role of technology in the delivery of evidence-based psychosocial treatment. Psychiatr Clin North Am. 2012;35:481–493. [PMC free article] [PubMed]
100. Eisenberger NI, Cole SW. Social neuroscience and health: neurophysiological mechanisms linking social ties with physical health. Nat Neurosci. 2012;15:669–674. [PubMed]
101. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68:815–834. [PMC free article] [PubMed]