Neurobiology of Addiction,” in Textbook of Substance Drive for the Drug-Taking Behavior Shifts from Positive Abuse Treatment

Neurobiology of George F. Koob, Ph.D. Addiction

CONCEPTUAL FRAMEWORK, different stages of the addiction cycle. While much SYNTHESIS CLINICAL DEFINITIONS, AND ANIMAL MODELS focus in animal studies has been on the synaptic sites and transductive mechanisms in the nervous system Drug addiction, also known as substance dependence, on which drugs with dependence potential act initially is a chronically relapsing disorder characterized by (1) to produce their acute positive reinforcing effects compulsion to seek and take the drug, (2) loss of con- (binge/intoxication stage), new animal models of trol in limiting intake, and (3) emergence of a negative chronic drug taking and seeking (withdrawal/negative emotional state (e.g., dysphoria, anxiety, irritability) affect stage) and the craving stage (preoccupation/antic- when access to the drug is prevented (defined here as ipation) have been developed and are beginning to be dependence) (1). Addiction and substance dependence used to explore how the nervous system adapts to drug (as currently defined by the Diagnostic and Statistical use (Table 1). The neurobiological mechanisms of ad- Manual of Mental Disorders, 4th edition) (2) will be diction that are involved in various stages of the addic- used interchangeably throughout this paper to refer to tion cycle have a specific focus on certain brain circuits a final stage of a usage process that moves from drug and the molecular/neurochemical changes associated use to addiction. Clinically, the occasional but limited with those circuits during the transition from drug- use of a drug with the potential for abuse or depen- taking to drug addiction and how those changes per- dence is distinct from escalated drug use and the emer- sist in the vulnerability to relapse (5). gence of a chronic drug-dependent state. An important goal of current neurobiological research is to NEUROBIOLOGICAL MECHANISMS OF understand the neuropharmacological and neuroad- THE BINGE/INTOXICATION STAGE aptive mechanisms within specific neurocircuits that mediate the transition from occasional, controlled A long-hypothesized key element of drug addic- drug use and the loss of behavioral control over drug- tion is that drugs of abuse activate brain reward seeking and drug-taking that defines chronic addic- systems, and understanding the neurobiological tion. bases for acute drug reward has been a key to how Addiction has been conceptualized as a chronic re- these systems change with the development of ad- lapsing disorder with roots both in impulsivity and diction (1, 6). A principle focus of research on the compulsivity and neurobiological mechanisms that neurobiology of the positive reinforcing effects of change as an individual moves from one domain to drugs with addiction potential has been the origins the other (3). In addiction, drug-taking behavior pro- and terminal areas of the mesocorticolimbic dopa- gresses from impulsivity to compulsivity in a three- mine system, and there is compelling evidence for stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. As individuals move from an impulsive to a compulsive disorder, the Adapted and updated from Koob G: “Neurobiology of Addiction,” in Textbook of Substance drive for the drug-taking behavior shifts from positive Abuse Treatment. Galanter M, Kleber HD (eds). Washington, DC, American Psychiatric Publishing, to negative reinforcement (Figure 1). Impulsivity and 2008, pp 3–16. compulsivity can coexist in different stages of the addiction cycle. CME Disclosure George F. Koob, Ph.D., Committee on the Neurobiology of Addictive Disorders, The Scripps Much of the recent progress in understanding the Research Institute, La Jolla, CA neurobiology of addiction has derived from the study of animal models of addiction on specific drugs such Dr. Koob reports the following: Advisory Board: Addex Pharmaceuticals; Consultant: Alkermes, as opiates, psychostimulants, and alcohol (4). While Arkeo Pharmaceuticals, Case Palmera, Embera Neuro Therapeutics, GlaxoSmithKline, Lilly, no animal model of addiction fully emulates the hu- Psychogenics. man condition, animal models do permit investiga- Address correspondence to George F. Koob, Ph.D., Committee on the Neurobiology of Addictive tion of specific elements of the process of drug addic- Disorders, The Scripps Research Institute, 10550 North Torrey Pines Rd., SP30-2400, La Jolla, tion. Such elements can be categorized by models of CA 92037; e-mail: [email protected]

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Figure 1.

(Top left) Diagram showing the stages of impulse control disorder and compulsive disorder cycles related to the sources of reinforcement. In impulse control disorders, an increasing tension and arousal occurs before the impulsive act, with pleasure, gratiﬁcation, or relief during the act. Following the act, there may or may not be regret or guilt. In compulsive disorders, there are recurrent and persistent thoughts (obsessions) that cause marked anxiety and stress followed by repetitive behaviors (compulsions) that are aimed at preventing or reducing distress (2). Positive reinforcement (pleasure/gratiﬁcation) is more closely associated with impulse control disorders. Negative reinforcement (relief of anxiety or relief of stress) is more closely associated with compulsive disorders. (Top right) Collapsing the cycles of impulsivity and compulsivity results in the addiction cycle, conceptualized as three major components: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. [Taken with permission from Koob GF, Everitt BJ, Robbins TW: Reward, motivation, and addiction, in Fundamental Neuroscience, 3rd ed. Edited by Squire LG, Berg D, Bloom FE, Du Lac S, Ghosh A, Spitzer N. Amsterdam, Academic Press, 2008, pp 987-1016.] (Bottom) Change in the relative contribu- tion of positive and negative reinforcement constructs during the development of substance dependence on alcohol.

the importance of this system in drug reward. the medial shell region of the nucleus accumbens, Much work suggests that activation of the mesocor- the role of dopamine becomes less critical as one ticolimbic dopamine system has multiple func- moves to opioid drugs, alcohol, and ⌬9-tetrahydro- tional attributes, including giving incentive salience cannabinol (⌬9-THC). Here, other neurotransmit- to stimuli in the environment (7) to drive perfor- ter systems such as opioid peptides, GABA, and mance of goal-directed behavior (8) or activation in endocannabinoids may play key roles either in se- general (9). However, the specific circuitry associ- ries or independent of activation of the mesolimbic ated with drug reward in general has been broad- dopamine system. Other components of the basal ened to include the many neural inputs and outputs forebrain that have been identified with drug re- that interact with the basal forebrain, specifically ward have also focused on the amygdala (5, 10). For the nucleus accumbens (Figure 2). As the neural example, a particularly sensitive site for blockade of circuits for the reinforcing effects of drugs with de- the acute reinforcing effects of alcohol with opioid pendence potential have evolved, the role of neu- and GABA-ergic antagonists appears to be the cen- rotransmitters/neuromodulators also has evolved, tral nucleus of the amygdala (11). Opioid peptide and four of those systems have been identified to antagonists also block the reinforcing effects of ⌬9- have a role in the acute reinforcing effects of drugs: THC, a key active ingredient in marijuana. Canna- ␥ dopamine, opioid peptides, -aminobutyric acid binoid CB1 antagonists block opioid, alcohol, and (GABA), and endocannabinoids (Table 2). cannabinoid reward (12, 13). In summary, all The mesolimbic dopamine system is well estab- drugs of abuse activate the mesolimbic dopamine lished as having a critical role in the activating and system, but much evidence suggests that dopamine- reinforcing effects of indirect sympathomimetics independent reinforcement occurs at the level of such as cocaine, methamphetamine, and nicotine. the nucleus accumbens, suggesting multiple inputs However, while all drugs of abuse acutely activate to the activation of critical reinforcement circuitry the mesolimbic dopamine system, particularly in in these brain regions (14, 15). Thus, multiple neu-

56 Winter 2011, Vol. IX, No. 1 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY KOOB rotransmitters are implicated in the acute reinforc- Table 1. Animal Models of the Three ing effects of drugs of abuse. Key players in the Stages of the Addiction Cycle nucleus accumbens and amygdala are dopamine, opioid peptide, and GABA systems with modula- Stage of Addiction Cycle Animal Models tion via endocannabinoids. Binge/intoxication Drug/alcohol self-administration Other elements of the acute drug reward circuit Conditioned place preference include the ventral pallidum and dorsal striatum. A Brain stimulation reward thresholds major output from the nucleus accumbens is to the Increased motivation for self-administration ventral pallidum/substantia innominata, and ele- in dependent animals ments of the ventral pallidum may not only be crit- Withdrawal/negative affect Anxiety-like responses ical for further processing of the drug reward signal Conditioned place aversion SYNTHESIS CLINICAL but also may be directly modulated by drugs of Withdrawal-induced drug self- abuse (16, 17). The dorsal striatum does not appear administration to play a major role in the acute reinforcing effects Preoccupation/anticipation Drug-induced reinstatement of drugs of abuse but appears to be recruited during Cue-induced reinstatement the development of compulsive drug seeking (18), Stress-induced reinstatement suggesting that the dorsal striatum may play a mi- nor role in the acute reinforcing effects of psychostimulant drugs but a key role in the transition to reinforcement mechanisms associated with the de- compulsive use (18). velopment of addiction. The extended amygdala is In summary, much is known about the neurobi- composed of the bed nucleus of the stria terminalis, ological circuitry of drug reward. The starting point the central nucleus of the amygdala, and a transi- for the reward circuit is the medial forebrain bun- tion zone in the medial subregion of the nucleus dle, composed of myelinated fibers that bidirec- accumbens (shell of the nucleus accumbens). Each tionally connect the olfactory tubercle and nucleus of these regions has cytoarchitectural and circuitry accumbens with the hypothalamus and ventral teg- similarities (20). The extended amygdala receives mental area (19), and includes ascending mono- numerous afferents from limbic structures, such as amine pathways such as the mesocorticolimbic do- the basolateral amygdala and hippocampus, and pamine system (14). The initial action of drug sends efferents to the medial part of the ventral reward is hypothesized to depend on dopamine re- pallidum and a large projection to the lateral hypo- lease in the nucleus accumbens for cocaine, am- thalamus, thus further defining the specific brain phetamine, and nicotine, opioid peptide receptor areas that interface classical limbic (emotional) activation in the ventral tegmental area (via dopa- structures with the extrapyramidal motor system mine activation) and nucleus accumbens (indepen- (21). The extended amygdala has long been hy- dent of dopamine activation) for opiates, and pothesized to play a key role not only in fear con-

GABAA systems in the nucleus accumbens and ditioning (22) but also in the emotional compo- amygdala for alcohol. The nucleus accumbens is nent of pain processing (23). situated strategically to receive important limbic in- The neural substrates and neuropharmacological formation from the amygdala, frontal cortex, and mechanisms for the negative motivational effects of hippocampus that could be converted to motiva- drug withdrawal may involve disruption of the same tional action via its connections with the extrapy- neural systems implicated in the positive reinforcing ramidal motor system. Thus, an early critical role of effects of drugs but also involve recruitment of antire- the nucleus accumbens was established for the ward systems (see below). Measures of brain reward acute reinforcing effects of drugs, with a supporting function during acute abstinence from all major drugs role of the central nucleus of the amygdala and with dependence potential have revealed increases in ventral pallidum. brain reward thresholds measured by direct brain stimulation reward (24–29). These increases in reward thresholds may reflect decreases in the activity of NEUROBIOLOGICAL MECHANISMS OF reward neurotransmitter systems in the midbrain and THE WITHDRAWAL/NEGATIVE AFFECT STAGE forebrain implicated in the positive reinforcing effects of drugs. The neuroanatomical entity termed the extended Changes at the neurochemical level that reflect amygdala (20) may represent a common anatomi- changes in the neurotransmitter system implicated in cal substrate that integrates brain arousal-stress sys- acute drug reward have been hypothesized to reflect a tems with hedonic processing systems to produce within-system neuroadaptation and contribute signif- the negative emotional states that drive negative icantly to the negative motivational state associated

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Figure 2.

Drugs of abuse, despite diverse initial actions, produce some common effects on the ventral tegmental area (VTA) and nucleus accumbens (NAc). Stimulants directly increase dopaminergic transmission in the NAc. Opiates do the same indirectly: they inhibit GABA-ergic interneurons in the VTA, which disinhibits VTA dopa-

mine neurons. Opiates also directly act on opioid receptors on NAc neurons, and opioid receptors, such as D2 dopamine (DA) receptors, signal via Gi; hence, the two mechanisms converge within some NAc neurons. The actions of the other drugs remain more conjectural. Nicotine appears to activate VTA dopamine neurons directly via stimulation of nicotinic cholinergic receptors on those neurons and indirectly via stimulation of its receptors on glutamatergic nerve terminals that in-

nervate the dopamine cells. Alcohol, by promoting GABAA receptor function, may inhibit GABA-ergic terminals in the VTA and disinhibit VTA dopamine neurons. It may similarly inhibit glutamatergic terminals that innervate NAc neurons. Many additional mechanisms (not shown) are proposed for alcohol. Cannabinoid mecha-

nisms are complex and involve the activation of cannabinoid CB1 receptors (which, similar to D2 and opioid receptors, are Gi-linked) on glutamatergic and GABA- ergic nerve terminals in the NAc and on NAc neurons themselves. Phencyclidine (PCP) may act by inhibiting postsynaptic NMDA glutamate receptors in the NAc. Finally, evidence shows that nicotine and alcohol may activate endogenous opioid pathways and that these and other drugs of abuse (such as opiates) may activate endogenous cannabinoid pathways (not shown). PPT/LDT, peduncular pontine tegmentum/lateral dorsal tegmentum. [Taken with permission from Nestler EJ: Is there a common molecular pathway for addiction? Nat Neurosci 2005; 8:1445–1449.]

with acute drug abstinence. A within-system neuroad- chemical systems other than those involved in the aptation can be deﬁned as “the primary cellular re- positive rewarding effects of drugs of abuse are response element to the drug would itself adapt to neu- cruited or dysregulated by chronic activation of the tralize the drug’s effects; persistence of the opposing reward system (30). Brain neurochemical systems effects after the drug disappears would produce the involved in stress modulation may also be engaged withdrawal response” (30). Such within-system within the neurocircuitry of the brain stress systems changes include decreases in dopaminergic transmis- in an attempt to overcome the chronic presence of sion in the nucleus accumbens during drug with- the perturbing drug and to restore normal function drawal measured by in vivo microdialysis (31, 32), despitethepresenceofdrug.Boththehypothalamic- increased sensitivity of opioid receptor transduction pituitary-adrenal axis and the brain stress system mechanisms in the nucleus accumbens during opioid mediated by corticotropin-releasing factor (CRF) withdrawal (33), decreased GABA-ergic and in- are dysregulated by chronic administration of all creased N-methyl-D-aspartate (NMDA) glutamater- major drugs with dependence or abuse potential, gic transmission during alcohol withdrawal (34–37), with a common response of elevated ACTH, corti- and differential regional changes in nicotinic receptor costerone, and amygdala CRF during acute with- function (38, 39). The decreased reward system func- drawal (40–45) (Table 3). Acute withdrawal from tion may persist in the form of long-term biochemical drugs may also increase the release of norepineph- changes that contribute to the clinical syndrome of rine in the bed nucleus of the stria terminalis and protracted abstinence and vulnerability to relapse. decrease levels of neuropeptide Y in the central and The emotional dysregulation associated with the medial nuclei of the amygdala (46). withdrawal/negative affect stage also may involve a These results suggest, during the development of between-system neuroadaptation, in which neuro- dependence, not only a change in the function of

58 Winter 2011, Vol. IX, No. 1 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY KOOB neurotransmitters associated with the acute rein- Table 2. Neurobiological Substrates for forcing effects of drugs (dopamine, opioid peptides, the Acute Reinforcing Effects of Drugs serotonin, GABA, and endocannabinoids) but also of Abuse recruitment of the brain stress system (CRF and norepinephrine) and dysregulation of the neuro- Drug of Abuse Neurotransmitter Site peptide Y brain antistress system (5) (Figure 3). Cocaine and Dopamine Nucleus accumbens Additionally, activation of the brain stress systems amphetamines ␥-Aminobutyric acid Amygdala may not only contribute to the negative motiva- Opioids Opioid peptides Nucleus accumbens tional state associated with acute abstinence but Dopamine Ventral tegmental area also may contribute to the vulnerability to stressors Endocannabinoids observed during protracted abstinence in humans. Nicotine Dopamine Nucleus accumbens SYNTHESIS CLINICAL Another candidate for the aversive effects of drug ␥-Aminobutyric acid Ventral tegmental area withdrawal is the opioid peptide dynorphin. Much Opioid peptides Amygdala evidence shows that dynorphin is increased in the ⌬9-Tetrahydrocannabinol Endocannabinoids Nucleus accumbens nucleus accumbens in response to dopaminergic Opioid peptides Ventral tegmental area activation and, in turn, that overactivity of dynor- Dopamine phin systems can decrease dopaminergic function. Alcohol Dopamine Nucleus accumbens ␬ opioid agonists are aversive, and cocaine, opioid, Opioid peptides Ventral tegmental area and ethanol withdrawal is associated with increased ␥-Aminobutyric acid Amygdala dynorphin in the nucleus accumbens or amygdala. Glutamate Dynorphin systems may also interact with the brain Endocannabinoids CRF systems and evidence shows that dynorphin drives CRF and CRF drives dynorphin (47). as a chronic relapsing disorder. Although often The concept of an antireward system has been linked to the construct of craving, craving per se has formulated to accommodate the significant been difficult to measure in human clinical studies changes in brain emotional systems associated (50) and often does not correlate with relapse. Nev- with the development of dependence (48). The ertheless, the stage of the addiction cycle in which antireward concept is based on the hypothesis the individual reinstates drug-seeking behavior af- that there are brain systems in place to limit re- ter abstinence remains a challenging focus for neu- ward (30), an opponent process concept that robiological mechanisms and medications develop- forms a general feature of biological systems. The ment for treatment. concept of an antireward system is derived from Animal models of craving can be divided into the hypothesis of between-system neuroadapta- two domains: drug seeking induced by stimuli tions to activation of the reward system at the paired with drug-taking and drug seeking induced neurocircuitry level. A between-system neuroad- by an acute stressor or a state of stress (Table 4). aptation is a circuitry change in which circuit B Craving Type-1 animal models involve the use of (antireward circuit) is activated by circuit A (re- drug-primed reinstatement and cue-induced rein- ward circuit) (Figure 4). This concept has its statement. Craving Type-2 animal models involve origins in the theoretical pharmacology that pre- stress-induced reinstatement in animals that have dates opponent process theory (49). Thus, the activation of brain stress systems such as CRF, Table 3. Common Withdrawal Features of norepinephrine, and dynorphin with concomi- Drugs of Abuse tant dysregulation of the neuropeptide Y system may represent the recruitment of an antireward Effect during Withdrawal system in the extended amygdala that produces Extracellular CRF the motivational components of drug withdrawal in the Central and provides a baseline hedonic shift that facili- Nucleus tates craving mechanisms (48). Brain Stimulation of the Anxiety-Like Drug Reward Thresholds Amygdala Responses Cocaine 111 NEUROBIOLOGICAL MECHANISMS OF THE PREOCCUPATION/ANTICIPATION Opioids 111 STAGE Ethanol 111 The preoccupation/anticipation stage of the addic- Nicotine 111 tion cycle has long been hypothesized to be a key ⌬9-Tetrahydrocannabinol 111 element of relapse in humans and defines addiction

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Figure 3.

Neurocircuitry associated with the acute positive reinforcing effects of drugs of abuse and the negative reinforcement of dependence and how it changes in the transition from nondependent drug taking to dependent drug taking. Key elements of the reward circuit are dopamine and opioid peptide neurons that intersect at both the ventral tegmental area and nucleus accumbens and are activated during initial use and the early binge/intoxication stage. Key elements of the stress circuit are CRF and noradrenergic neurons that converge on GABA interneurons in the central nucleus of the amygdala and are activated during the development of dependence. DA, dopamine; NE, norepinephrine; GABA, ␥-aminobutyric acid; CRF, corticotropin-releasing factor [Modiﬁed with permission from Koob GF, Le Moal M: Neurobiological mechanisms for opponent motivational processes in addiction. Philos Trans R Soc B Biol Sci 2008; 363:3113–3123.]

acquired drug self-administration and then have pus (60). Human subjects with cocaine addiction been subjected to extinction of responding for the show impaired performance in tasks that involve drug (51). attention, cognitive flexibility, and delayed reward Most evidence from animal studies suggests that discounting that are mediated by the medial and drug-induced reinstatement is localized to the me- orbital prefrontal cortex, as well as spatial, verbal, dial prefrontal cortex/nucleus accumbens/ventral and recognition memory impairments that are me- pallidum circuit mediated by the neurotransmitter diated by the hippocampus, and these deficits can glutamate (52). In contrast, neuropharmacological predict poor treatment outcomes (61, 62). Parallel and neurobiological studies using animal models animal studies of the orbitofrontal cortex, prefron- for cue-induced reinstatement involve the basolat- tal cortex, and hippocampus in addiction have be- eral amygdala as a critical substrate with a possible gun to show some of the deficits reflected in human feed-forward mechanism through the prefrontal studies. Experimenter-administered cocaine pro- cortex system involved in drug-induced reinstate- duced impairments in reversal learning (an orbito- ment (53, 54). Neurotransmitter systems involved frontal task) in rats and monkeys (63–65). Perhaps in drug-induced reinstatement involve a glutama- even more compelling, animals allowed extended tergic projection from the frontal cortex to the nu- access, but not limited access, to cocaine showed cleus accumbens that is modulated by dopamine deficits in working memory (a prefrontal cortex- activity in the frontal cortex. Cue-induced rein- dependent task), a sustained attention task (a pre- statement involves dopamine modulation in the frontal cortex-dependent task), and an objection basolateral amygdala and a glutamatergic projec- recognition task (a hippocampus-dependent task) tion to the nucleus accumbens from both the baso- (66–68). lateral amygdala and ventral subiculum (53, 55). In contrast, stress-induced reinstatement of drug-re- OVERALL NEUROCIRCUITRY OF lated responding in animal models appears to de- ADDICTION pend on the activation of both CRF and norepinephrine in elements of the extended amygdala In summary, three neurobiological circuits have (central nucleus of the amygdala and bed nucleus of been identified that have heuristic value for the the stria terminalis) (56, 57). Protracted abstinence, study of the neurobiological changes associated largely described in alcohol dependence models, with the development and persistence of drug de- appears to involve overactive glutamatergic and pendence (Figure 4). The acute reinforcing effects CRF systems (58, 59). of drugs of abuse that comprise the binge/intoxica- In humans, cognitive deficits with addiction are tion stage most likely involve actions with an em- observed that reflect the function of the medial pre- phasis on the reward system and inputs from the frontal cortex, orbitofrontal cortex, and hippocam- ventral tegmental area and arcuate nucleus of the

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Figure 4. SYNTHESIS CLINICAL

Neurocircuitry schematic illustrating the combination of neuroadaptations in the brain circuitry for the three stages of the addiction cycle that drive drug seeking behavior in the addicted state. Note the activation of the ventral striatum/dorsal striatum/extended amygdala driven by cues via hippocampal and basolateral amygdala and stress via the insula. The frontal cortex system is compromised, producing deficits in executive function and contributing to the incentive salience of drugs compared to natural reinforcers. Dopamine systems are compromised, and brain stress systems such as CRF are activated to reset further the salience of drugs and drug-related stimuli in the context of an aversive dysphoric state. AC, anterior cingulate; Acb, nucleus accumbens; AMG, amygdala; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CRF, corticotropin-releasing factor; DA, dopamine; DGP, dorsal globus pallidus; DS, dorsal striatum; GP, globus pallidus; Hippo, hippocampus; mPFC, medial prefrontal cortex; NE, norepinephrine; OFC, orbitofrontal cortex; SNc, substantia nigra pars compacta; Thal, thalamus; VGP, ventral globus pallidus; VS, ventral striatum. [Modified with permission from Koob GF: Neurobiology of addiction, in Textbook of Substance Abuse Treat- ment, 4th ed. Edited by Galanter M, Kleber HD. Washington DC, American Psychiatric Publishing, 2008, pp 3–16.] hypothalamus. In contrast, the symptoms of lel to the neuroplasticity of the neurocircuitry are acute withdrawal important for addiction, such the molecular changes that occur in these same as negative affect and increased anxiety associ- structures. Chronic exposure to opiates and cocaine ated with the withdrawal/negative affect stage, leads to activation of cyclic adenosine monophos- most likely involve decreases in function of the phate response-element binding protein (CREB) in extended amygdala system but also a recruitment the nucleus accumbens and central nucleus of the of brain stress neurocircuitry therein. The crav- amygdala (69, 70). CREB can be phosphorylated ing stage or preoccupation/anticipation stage in- by protein kinase A and by protein kinase regulated volves key afferent projections to the nucleus ac- by growth factors, putting it at a point of conver- cumbens and amygdala, specifically the gence for several intracellular messenger pathways prefrontal cortex (for drug-induced reinstate- that can regulate gene expression. Activation of ment) and the basolateral amygdala (for cue-in- CREB in the nucleus accumbens with psycho- duced reinstatement). Compulsive drug-seeking stimulant drugs is linked to the motivational symp- behavior is hypothesized to be perpetuated by toms of psychostimulant withdrawal, such as dys- ventral striatal-ventral pallidal-thalamic-cortical phoria, possibly through the induction of the loops. opioid peptide dynorphin, which binds to ␬ opioid receptors and has been hypothesized to represent a mechanism of motivational tolerance and depen- MOLECULAR AND CELLULAR TARGETS WITHIN THE BRAIN CIRCUITS dence (15). Repeated CREB activation drives ASSOCIATED WITH ADDICTION dynorphin expression in the nucleus accumbens, which in turn decreases dopaminergic activity and The focus of the present review is on the neuro- may activate other brain stress systems, all of which plasticity of addiction that involves alterations in can contribute to negative emotional states. Extra- specific neurochemical systems in the context of the cellular signal-regulated kinase (ERK) is another three stages of the addiction cycle. However, paral- key element of intracellular signaling that is consid-

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Table 4. Drug Craving activation of members of the Fos protein family, Drug craving “Drug craving is the desire for the previously such as c-fos, FosB, Fra-1, and Fra-2 in the nu- experienced effects of a psychoactive cleus accumbens, other transcription factors and substance. This desire can become isoforms of ⌬FosB (i.e., a highly stable form of compelling and can increase in the FosB) have been shown to accumulate over lon- presence of both internal and external cues, particularly with perceived ger periods of time (days) with repeated drug substance availability. It is characterized administration (15). Animals with activated by an increased likelihood of drug-seeking ⌬FosB have exaggerated sensitivity to the re- behaviour and, in humans, of drug-related warding effects of drugs of abuse, and ⌬FosB has thoughts.” (United Nations International been hypothesized to act as a sustained molecular Drug Control Programme, 1992) “switch” that helps initiate and maintain a state Craving Type-1 Induced by stimuli that have been paired of addiction (77). Whether (and how) such tran- with drug self-administration such as scription factors influence the function of the environmental cues Termed conditioned positive reinforcement in brain stress systems, such as CRF, dynorphin, experimental psychology neuropeptide Y, and the others described above, Animal model: Cue-induced reinstatement remains to be further explored. where a cue previously paired with access to a drug reinstates responding for a lever that has been extinguished BRAIN IMAGING CIRCUITS INVOLVED IN HUMAN ADDICTION Craving Type-2 State of protracted abstinence in drug- dependent individuals weeks after acute Brain imaging studies using positron emission withdrawal. Conceptualized as a state change tomography with ligands for measuring oxygen characterized by anxiety and dysphoria. utilization or glucose metabolism or using MRI Animal model: Residual hypersensitivity to techniques are providing dramatic insights into states of stress and environmental the neurocircuitry changes in the human brain stressors that lead to relapse to drug- associated with the development, maintenance, seeking behavior and vulnerability to addiction. These imaging results overall show a striking resemblance to the ered a key component in the plasticity associated neurocircuitry identified by human studies. Dur- with repeated administration of cocaine, specifi- ing acute intoxication with alcohol, nicotine, cally behavioral sensitization, cocaine reward, and and cocaine, there is an activation of the orbito- time-dependent increases in cocaine seeking after frontal cortex, prefrontal cortex, anterior cingu- withdrawal (i.e., incubation effect) (71, 72). late, extended amygdala, and ventral striatum. Another molecular target for regulating the plastic- This activation is often accompanied by an in- ity that leads to addiction is dysregulation of cystine- crease in availability of the neurotransmitter do- glutamate exchange, which is hypothesized to drive pamine. During acute and chronic withdrawal, a pathological glutamate signaling related to several reversal of these changes occurs, with decreases in components of the addiction cycle. Repeated admin- metabolic activity, particularly in the orbitofron- istration of cocaine blunts cystine-glutamate ex- tal cortex, prefrontal cortex, and anterior cingu- change, leading to reduced basal and increased co- late, and decreases in basal dopamine activity as

caine-induced glutamate in the nucleus accumbens measured by decreased D2 receptors in the ven- that persists for at least 3 weeks after the last cocaine tral striatum and prefrontal cortex. Cue-induced treatment (73). Most compelling is the observation reinstatement appears to involve the reactivation that treatment with N-acetylcysteine, by activating of these circuits, much like acute intoxication cystine-glutamate exchange, prevented cocaine-in- (78–80). Craving or cues associated with co- duced escalation and behavioral sensitization, restored caine and nicotine activated the prefrontal cortex the ability to induce long-term potentiation and long- and anterior cingulate gyrus (81, 82). Imaging term depression in the nucleus accumbens, and studies also show evidence that cues associated blunted reinstatement in animals and conditioned re- with cocaine craving increase dopamine release activity to drug cues in humans (74–76). in the striatum as well as opioid peptides in the Finally, CREB and other intracellular messen- anterior cingulate and frontal cortex (83–85). gers can activate transcription factors, which can Craving in alcoholics appears to be correlated change gene expression and produce long-term with higher opioid peptide activity in the stria- changes in protein expression, and, as a result, neu- tum but lower dopaminergic activity (86, 87). ronal function. Although acute administration of Thus, imaging studies reveal baseline decreases drugs of abuse can cause rapid (within hours) in orbitofrontal function and dopamine function

62 Winter 2011, Vol. IX, No. 1 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY KOOB during dependence but the reactivation of dopa- imaging studies reveal similar neurocircuits in- mine and reward system function during acute volved in acute intoxication, chronic drug depen- craving episodes, consistent with the early for- dence, and vulnerability to relapse. mulation of different neural substrates for crav- Although no exact imaging results necessarily ing Type-1 and Type-2 (see above). predict addiction, two salient changes in established and unrecovered substance-dependent indi- SUMMARY AND CONCLUSIONS viduals that cut across different drugs are decreases in orbitofrontal/prefrontal cortex function and de-

Much progress in neurobiology has provided a creases in brain dopamine D2 receptors. No molec- useful neurocircuitry framework with which to ular markers are sufficiently specific to predict the identify the neurobiological and neuroadaptive vulnerability to addiction, but changes in certain SYNTHESIS CLINICAL mechanisms involved in the development of drug intermediate early genes with chronic drug expo- addiction. The brain reward system implicated in sure in animal models show promise of long-term the development of addiction is composed of key changes in specific brain regions that may be com- elements of the basal forebrain with a focus on the mon to all drugs of abuse. The continually evolving nucleus accumbens and central nucleus of the knowledge base of the biological and neurobiolog- amygdala. Neuropharmacological studies in animal ical aspects of substance use disorders provides a models of addiction have provided evidence for the heuristic framework to better develop diagnoses, activation of specific neurochemical mechanisms in specific brain reward neurochemical systems in the prevention, and treatment of substance abuse dis- basal forebrain (dopamine, opioid peptides, orders. GABA, and endocannabinoids) during the binge/ intoxication stage. During the withdrawal/negative affect stage, dysregulation of the same brain reward A CKNOWLEDGMENT neurochemical systems occurs in the basal forebrain Research was supported by National Institutes of Health grants AA06420 and (dopamine, opioid peptides, GABA, and endocan- AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA04043, DA04398, DA10072 and DA023597 from the National Institute on nabinoids). There is also recruitment of brain Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive stress/aversion systems (CRF and dynorphin) and and Kidney Diseases. Research also was supported by the Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute. The dysregulation of brain antistress systems (neuro- author thanks Michael Arends and Mellany Santos for their assistance with peptide Y) that contribute to the negative motiva- manuscript preparation. This is publication number 21077 from The Scripps tional state associated with drug abstinence. Research Institute. During the preoccupation/anticipation stage, neurobiological circuits that engage the frontal cortex KEY POINTS glutamatergic projections to the nucleus accumbens are critical for drug-induced reinstatement, ● The brain reward system implicated in the de- whereas basolateral amygdala and ventral subicu- velopment of addiction is composed of key lum glutamatergic projections to the nucleus ac- elements of the basal forebrain that include the cumbens are involved in cue-induced reinstate- ventral striatum, the extended amygdala, and ment. Stress-induced reinstatement appears to be its connections. mediated by changes in the antireward systems of ● Neuropharmacological studies in animal the extended amygdala. The changes in craving and models of addiction have provided evidence antireward (stress) systems are hypothesized to re- for the decreases of specific neurochemical main outside of a homeostatic state, and as such mechanisms in specific brain reward neuro- convey the vulnerability for the development of de- chemical systems in the ventral striatum and pendence and relapse in addiction. Genetic studies amygdala (dopamine, opioid peptides, GABA, to date in animals suggest roles for the genes encod- and endocannabinoids). ing the neurochemical elements involved in the ● The recruitment of brain stress systems (CRF brain reward (dopamine, opioid peptide) and stress and norepinephrine) and dysregulation of (neuropeptide Y) systems in the vulnerability to brain anti-stress systems (neuropeptide Y) pro- addiction. Molecular studies have identified trans- vide the negative motivational state associated duction and transcription factors that may mediate with drug abstinence. the dependence-induced reward dysregulation ● Changes in the reward and stress systems are (CREB) and chronic-vulnerability changes hypothesized to maintain hedonic stability in (⌬FosB) in neurocircuitry associated with the de- an allostatic state (altered reward set point), as velopment and maintenance of addiction. Human opposed to a homeostatic state, and as such

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