George F. Koob, Ph.D.Neurobiology ofAddictionCONCEPTUAL FRAMEWORK,DEFINITIONS, AND ANIMAL MODELS

Drug addiction, also known as substance dependence,is a chronically relapsing disorder characterized by (1)compulsion to seek and take the drug, (2) loss of con-trol in limiting intake, and (3) emergence of a negativeemotional state (e.g., dysphoria, anxiety, irritability)when access to the drug is prevented (defined here asdependence) (1). Addiction and substance dependence(as currently defined by the Diagnostic and StatisticalManual of Mental Disorders, 4th edition) (2) will beused interchangeably throughout this paper to refer toa final stage of a usage process that moves from druguse to addiction. Clinically, the occasional but limiteduse of a drug with the potential for abuse or depen-dence is distinct from escalated drug use and the emer-gence of a chronic drug-dependent state. An impor-tant goal of current neurobiological research is tounderstand the neuropharmacological and neuroad-aptive mechanisms within specific neurocircuits thatmediate the transition from occasional, controlleddrug use and the loss of behavioral control over drug-seeking and drug-taking that defines chronic addic-tion.

Addiction has been conceptualized as a chronic re-lapsing disorder with roots both in impulsivity andcompulsivity and neurobiological mechanisms thatchange as an individual moves from one domain tothe other (3). In addiction, drug-taking behavior pro-gresses from impulsivity to compulsivity in a three-stage cycle: binge/intoxication, withdrawal/negative af-fect, and preoccupation/anticipation. As individualsmove from an impulsive to a compulsive disorder, thedrive for the drug-taking behavior shifts from positiveto negative reinforcement (Figure 1). Impulsivity andcompulsivity can coexist in different stages of the ad-diction cycle.

Much of the recent progress in understanding theneurobiology of addiction has derived from the studyof animal models of addiction on specific drugs suchas opiates, psychostimulants, and alcohol (4). Whileno animal model of addiction fully emulates the hu-man condition, animal models do permit investiga-tion of specific elements of the process of drug addic-tion. Such elements can be categorized by models of

different stages of the addiction cycle. While muchfocus in animal studies has been on the synaptic sitesand transductive mechanisms in the nervous systemon which drugs with dependence potential act initiallyto produce their acute positive reinforcing effects(binge/intoxication stage), new animal models ofchronic drug taking and seeking (withdrawal/negativeaffect stage) and the craving stage (preoccupation/antic-ipation) have been developed and are beginning to beused to explore how the nervous system adapts to druguse (Table 1). The neurobiological mechanisms of ad-diction that are involved in various stages of the addic-tion cycle have a specific focus on certain brain circuitsand the molecular/neurochemical changes associatedwith those circuits during the transition from drug-taking to drug addiction and how those changes per-sist in the vulnerability to relapse (5).

NEUROBIOLOGICAL MECHANISMS OFTHE BINGE/INTOXICATION STAGE

A long-hypothesized key element of drug addic-tion is that drugs of abuse activate brain rewardsystems, and understanding the neurobiologicalbases for acute drug reward has been a key to howthese systems change with the development of ad-diction (1, 6). A principle focus of research on theneurobiology of the positive reinforcing effects ofdrugs with addiction potential has been the originsand terminal areas of the mesocorticolimbic dopa-mine system, and there is compelling evidence for

Adapted and updated from Koob G: “Neurobiology of Addiction,” in Textbook of SubstanceAbuse Treatment. Galanter M, Kleber HD (eds). Washington, DC, American Psychiatric Publishing,2008, pp 3–16.

CME DisclosureGeorge F. Koob, Ph.D., Committee on the Neurobiology of Addictive Disorders, The ScrippsResearch Institute, La Jolla, CA

Dr. Koob reports the following: Advisory Board: Addex Pharmaceuticals; Consultant: Alkermes,Arkeo Pharmaceuticals, Case Palmera, Embera Neuro Therapeutics, GlaxoSmithKline, Lilly,Psychogenics.

Address correspondence to George F. Koob, Ph.D., Committee on the Neurobiology of AddictiveDisorders, The Scripps Research Institute, 10550 North Torrey Pines Rd., SP30-2400, La Jolla,CA 92037; e-mail: gkoob@scripps.edu

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the importance of this system in drug reward.Much work suggests that activation of the mesocor-ticolimbic dopamine system has multiple func-tional attributes, including giving incentive salienceto stimuli in the environment (7) to drive perfor-mance of goal-directed behavior (8) or activation ingeneral (9). However, the specific circuitry associ-ated with drug reward in general has been broad-ened to include the many neural inputs and outputsthat interact with the basal forebrain, specificallythe nucleus accumbens (Figure 2). As the neuralcircuits for the reinforcing effects of drugs with de-pendence potential have evolved, the role of neu-rotransmitters/neuromodulators also has evolved,and four of those systems have been identified tohave a role in the acute reinforcing effects of drugs:dopamine, opioid peptides, �-aminobutyric acid(GABA), and endocannabinoids (Table 2).

The mesolimbic dopamine system is well estab-lished as having a critical role in the activating andreinforcing effects of indirect sympathomimeticssuch as cocaine, methamphetamine, and nicotine.However, while all drugs of abuse acutely activatethe mesolimbic dopamine system, particularly in

the medial shell region of the nucleus accumbens,the role of dopamine becomes less critical as onemoves to opioid drugs, alcohol, and �9-tetrahydro-cannabinol (�9-THC). Here, other neurotransmit-ter systems such as opioid peptides, GABA, andendocannabinoids may play key roles either in se-ries or independent of activation of the mesolimbicdopamine system. Other components of the basalforebrain that have been identified with drug re-ward have also focused on the amygdala (5, 10). Forexample, a particularly sensitive site for blockade ofthe acute reinforcing effects of alcohol with opioidand GABA-ergic antagonists appears to be the cen-tral nucleus of the amygdala (11). Opioid peptideantagonists also block the reinforcing effects of �9-THC, a key active ingredient in marijuana. Canna-binoid CB1 antagonists block opioid, alcohol, andcannabinoid reward (12, 13). In summary, alldrugs of abuse activate the mesolimbic dopaminesystem, but much evidence suggests that dopamine-independent reinforcement occurs at the level ofthe nucleus accumbens, suggesting multiple inputsto the activation of critical reinforcement circuitryin these brain regions (14, 15). Thus, multiple neu-

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 disor-ders, an increasing tension and arousal occurs before the impulsive act, with pleasure, gratification, or relief during the act. Following the act, there may or maynot be regret or guilt. In compulsive disorders, there are recurrent and persistent thoughts (obsessions) that cause marked anxiety and stress followed by repetitivebehaviors (compulsions) that are aimed at preventing or reducing distress (2). Positive reinforcement (pleasure/gratification) is more closely associated with impulsecontrol disorders. Negative reinforcement (relief of anxiety or relief of stress) is more closely associated with compulsive disorders. (Top right) Collapsing the cyclesof impulsivity and compulsivity results in the addiction cycle, conceptualized as three major components: preoccupation/anticipation, binge/intoxication, and with-drawal/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.

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rotransmitters are implicated in the acute reinforc-ing effects of drugs of abuse. Key players in thenucleus accumbens and amygdala are dopamine,opioid peptide, and GABA systems with modula-tion via endocannabinoids.

Other elements of the acute drug reward circuitinclude the ventral pallidum and dorsal striatum. Amajor output from the nucleus accumbens is to theventral pallidum/substantia innominata, and ele-ments of the ventral pallidum may not only be crit-ical for further processing of the drug reward signalbut also may be directly modulated by drugs ofabuse (16, 17). The dorsal striatum does not appearto play a major role in the acute reinforcing effectsof drugs of abuse but appears to be recruited duringthe development of compulsive drug seeking (18),suggesting that the dorsal striatum may play a mi-nor role in the acute reinforcing effects of psycho-stimulant drugs but a key role in the transition tocompulsive use (18).

In summary, much is known about the neurobi-ological circuitry of drug reward. The starting pointfor the reward circuit is the medial forebrain bun-dle, composed of myelinated fibers that bidirec-tionally connect the olfactory tubercle and nucleusaccumbens with the hypothalamus and ventral teg-mental area (19), and includes ascending mono-amine pathways such as the mesocorticolimbic do-pamine system (14). The initial action of drugreward is hypothesized to depend on dopamine re-lease in the nucleus accumbens for cocaine, am-phetamine, and nicotine, opioid peptide receptoractivation in the ventral tegmental area (via dopa-mine activation) and nucleus accumbens (indepen-dent of dopamine activation) for opiates, andGABAA systems in the nucleus accumbens andamygdala for alcohol. The nucleus accumbens issituated strategically to receive important limbic in-formation from the amygdala, frontal cortex, andhippocampus that could be converted to motiva-tional action via its connections with the extrapy-ramidal motor system. Thus, an early critical role ofthe nucleus accumbens was established for theacute reinforcing effects of drugs, with a supportingrole of the central nucleus of the amygdala andventral pallidum.

NEUROBIOLOGICAL MECHANISMS OFTHE WITHDRAWAL/NEGATIVE AFFECTSTAGE

The neuroanatomical entity termed the extendedamygdala (20) may represent a common anatomi-cal substrate that integrates brain arousal-stress sys-tems with hedonic processing systems to producethe negative emotional states that drive negative

reinforcement mechanisms associated with the de-velopment of addiction. The extended amygdala iscomposed of the bed nucleus of the stria terminalis,the central nucleus of the amygdala, and a transi-tion zone in the medial subregion of the nucleusaccumbens (shell of the nucleus accumbens). Eachof these regions has cytoarchitectural and circuitrysimilarities (20). The extended amygdala receivesnumerous afferents from limbic structures, such asthe basolateral amygdala and hippocampus, andsends efferents to the medial part of the ventralpallidum and a large projection to the lateral hypo-thalamus, thus further defining the specific brainareas that interface classical limbic (emotional)structures with the extrapyramidal motor system(21). The extended amygdala has long been hy-pothesized to play a key role not only in fear con-ditioning (22) but also in the emotional compo-nent of pain processing (23).

The neural substrates and neuropharmacologicalmechanisms for the negative motivational effects ofdrug withdrawal may involve disruption of the sameneural systems implicated in the positive reinforcingeffects of drugs but also involve recruitment of antire-ward systems (see below). Measures of brain rewardfunction during acute abstinence from all major drugswith dependence potential have revealed increases inbrain reward thresholds measured by direct brainstimulation reward (24–29). These increases in re-ward thresholds may reflect decreases in the activity ofreward neurotransmitter systems in the midbrain andforebrain implicated in the positive reinforcing effectsof drugs.

Changes at the neurochemical level that reflectchanges in the neurotransmitter system implicated inacute drug reward have been hypothesized to reflect awithin-system neuroadaptation and contribute signif-icantly to the negative motivational state associated

Table 1. Animal Models of the ThreeStages of the Addiction CycleStage of Addiction Cycle Animal Models

Binge/intoxication Drug/alcohol self-administrationConditioned place preferenceBrain stimulation reward thresholdsIncreased motivation for self-administration

in dependent animals

Withdrawal/negative affect Anxiety-like responsesConditioned place aversionWithdrawal-induced drug self-

administration

Preoccupation/anticipation Drug-induced reinstatementCue-induced reinstatementStress-induced reinstatement

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with acute drug abstinence. A within-system neuroad-aptation can be defined as “the primary cellular re-sponse element to the drug would itself adapt to neu-tralize the drug’s effects; persistence of the opposingeffects after the drug disappears would produce thewithdrawal response” (30). Such within-systemchanges include decreases in dopaminergic transmis-sion in the nucleus accumbens during drug with-drawal measured by in vivo microdialysis (31, 32),increased sensitivity of opioid receptor transductionmechanisms in the nucleus accumbens during opioidwithdrawal (33), decreased GABA-ergic and in-creased N-methyl-D-aspartate (NMDA) glutamater-gic transmission during alcohol withdrawal (34–37),and differential regional changes in nicotinic receptorfunction (38, 39). The decreased reward system func-tion may persist in the form of long-term biochemicalchanges that contribute to the clinical syndrome ofprotracted abstinence and vulnerability to relapse.

The emotional dysregulation associated with thewithdrawal/negative affect stage also may involve abetween-system neuroadaptation, in which neuro-

chemical systems other than those involved in thepositive rewarding effects of drugs of abuse are re-cruited or dysregulated by chronic activation of thereward system (30). Brain neurochemical systemsinvolved in stress modulation may also be engagedwithin the neurocircuitry of the brain stress systemsin an attempt to overcome the chronic presence ofthe perturbing drug and to restore normal functiondespitethepresenceofdrug.Boththehypothalamic-pituitary-adrenal axis and the brain stress systemmediated by corticotropin-releasing factor (CRF)are dysregulated by chronic administration of allmajor drugs with dependence or abuse potential,with a common response of elevated ACTH, corti-costerone, and amygdala CRF during acute with-drawal (40–45) (Table 3). Acute withdrawal fromdrugs may also increase the release of norepineph-rine in the bed nucleus of the stria terminalis anddecrease levels of neuropeptide Y in the central andmedial nuclei of the amygdala (46).

These results suggest, during the development ofdependence, not only a change in the function of

Figure 2.

Drugs of abuse, despite diverse initial actions, produce some common effects on the ventral tegmental area (VTA) and nucleus accumbens (NAc). Stimulants di-rectly 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, thetwo mechanisms converge within some NAc neurons. The actions of the other drugs remain more conjectural. Nicotine appears to activate VTA dopamine neuronsdirectly 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. Itmay 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 acti-vate endogenous cannabinoid pathways (not shown). PPT/LDT, peduncular pontine tegmentum/lateral dorsal tegmentum. [Taken with permission from Nestler EJ: Isthere a common molecular pathway for addiction? Nat Neurosci 2005; 8:1445–1449.]

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neurotransmitters associated with the acute rein-forcing effects of drugs (dopamine, opioid peptides,serotonin, GABA, and endocannabinoids) but alsorecruitment of the brain stress system (CRF andnorepinephrine) and dysregulation of the neuro-peptide Y brain antistress system (5) (Figure 3).Additionally, activation of the brain stress systemsmay not only contribute to the negative motiva-tional state associated with acute abstinence butalso may contribute to the vulnerability to stressorsobserved during protracted abstinence in humans.

Another candidate for the aversive effects of drugwithdrawal is the opioid peptide dynorphin. Muchevidence shows that dynorphin is increased in thenucleus accumbens in response to dopaminergicactivation and, in turn, that overactivity of dynor-phin systems can decrease dopaminergic function.� opioid agonists are aversive, and cocaine, opioid,and ethanol withdrawal is associated with increaseddynorphin in the nucleus accumbens or amygdala.Dynorphin systems may also interact with the brainCRF systems and evidence shows that dynorphindrives CRF and CRF drives dynorphin (47).

The concept of an antireward system has beenformulated to accommodate the significantchanges in brain emotional systems associatedwith the development of dependence (48). Theantireward concept is based on the hypothesisthat there are brain systems in place to limit re-ward (30), an opponent process concept thatforms a general feature of biological systems. Theconcept of an antireward system is derived fromthe hypothesis of between-system neuroadapta-tions to activation of the reward system at theneurocircuitry level. A between-system neuroad-aptation is a circuitry change in which circuit B(antireward circuit) is activated by circuit A (re-ward circuit) (Figure 4). This concept has itsorigins in the theoretical pharmacology that pre-dates opponent process theory (49). Thus, theactivation of brain stress systems such as CRF,norepinephrine, and dynorphin with concomi-tant dysregulation of the neuropeptide Y systemmay represent the recruitment of an antirewardsystem in the extended amygdala that producesthe motivational components of drug withdrawaland provides a baseline hedonic shift that facili-tates craving mechanisms (48).

NEUROBIOLOGICAL MECHANISMS OFTHE PREOCCUPATION/ANTICIPATIONSTAGE

The preoccupation/anticipation stage of the addic-tion cycle has long been hypothesized to be a keyelement of relapse in humans and defines addiction

as a chronic relapsing disorder. Although oftenlinked to the construct of craving, craving per se hasbeen difficult to measure in human clinical studies(50) and often does not correlate with relapse. Nev-ertheless, the stage of the addiction cycle in whichthe individual reinstates drug-seeking behavior af-ter abstinence remains a challenging focus for neu-robiological mechanisms and medications develop-ment for treatment.

Animal models of craving can be divided intotwo domains: drug seeking induced by stimulipaired with drug-taking and drug seeking inducedby an acute stressor or a state of stress (Table 4).Craving Type-1 animal models involve the use ofdrug-primed reinstatement and cue-induced rein-statement. Craving Type-2 animal models involvestress-induced reinstatement in animals that have

Table 2. Neurobiological Substrates forthe Acute Reinforcing Effects of Drugsof AbuseDrug of Abuse Neurotransmitter Site

Cocaine and Dopamine Nucleus accumbensamphetamines �-Aminobutyric acid Amygdala

Opioids Opioid peptides Nucleus accumbensDopamine Ventral tegmental areaEndocannabinoids

Nicotine Dopamine Nucleus accumbens�-Aminobutyric acid Ventral tegmental areaOpioid peptides Amygdala

�9-Tetrahydrocannabinol Endocannabinoids Nucleus accumbensOpioid peptides Ventral tegmental areaDopamine

Alcohol Dopamine Nucleus accumbensOpioid peptides Ventral tegmental area�-Aminobutyric acid AmygdalaGlutamateEndocannabinoids

Table 3. Common Withdrawal Features ofDrugs of Abuse

Drug

Effect during Withdrawal

Brain StimulationReward Thresholds

Extracellular CRFin the Central

Nucleusof the

AmygdalaAnxiety-LikeResponses

Cocaine 1 1 1

Opioids 1 1 1

Ethanol 1 1 1

Nicotine 1 1 1

�9-Tetrahydrocannabinol 1 1 1

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acquired drug self-administration and then havebeen subjected to extinction of responding for thedrug (51).

Most evidence from animal studies suggests thatdrug-induced reinstatement is localized to the me-dial prefrontal cortex/nucleus accumbens/ventralpallidum circuit mediated by the neurotransmitterglutamate (52). In contrast, neuropharmacologicaland neurobiological studies using animal modelsfor cue-induced reinstatement involve the basolat-eral amygdala as a critical substrate with a possiblefeed-forward mechanism through the prefrontalcortex system involved in drug-induced reinstate-ment (53, 54). Neurotransmitter systems involvedin drug-induced reinstatement involve a glutama-tergic projection from the frontal cortex to the nu-cleus accumbens that is modulated by dopamineactivity in the frontal cortex. Cue-induced rein-statement involves dopamine modulation in thebasolateral amygdala and a glutamatergic projec-tion to the nucleus accumbens from both the baso-lateral amygdala and ventral subiculum (53, 55). Incontrast, stress-induced reinstatement of drug-re-lated responding in animal models appears to de-pend on the activation of both CRF and norepi-nephrine in elements of the extended amygdala(central nucleus of the amygdala and bed nucleus ofthe stria terminalis) (56, 57). Protracted abstinence,largely described in alcohol dependence models,appears to involve overactive glutamatergic andCRF systems (58, 59).

In humans, cognitive deficits with addiction areobserved that reflect the function of the medial pre-frontal cortex, orbitofrontal cortex, and hippocam-

pus (60). Human subjects with cocaine addictionshow impaired performance in tasks that involveattention, cognitive flexibility, and delayed rewarddiscounting that are mediated by the medial andorbital prefrontal cortex, as well as spatial, verbal,and recognition memory impairments that are me-diated by the hippocampus, and these deficits canpredict poor treatment outcomes (61, 62). Parallelanimal studies of the orbitofrontal cortex, prefron-tal cortex, and hippocampus in addiction have be-gun to show some of the deficits reflected in humanstudies. Experimenter-administered cocaine pro-duced impairments in reversal learning (an orbito-frontal task) in rats and monkeys (63–65). Perhapseven more compelling, animals allowed extendedaccess, but not limited access, to cocaine showeddeficits in working memory (a prefrontal cortex-dependent task), a sustained attention task (a pre-frontal cortex-dependent task), and an objectionrecognition task (a hippocampus-dependent task)(66–68).

OVERALL NEUROCIRCUITRY OFADDICTION

In summary, three neurobiological circuits havebeen identified that have heuristic value for thestudy of the neurobiological changes associatedwith the development and persistence of drug de-pendence (Figure 4). The acute reinforcing effectsof drugs of abuse that comprise the binge/intoxica-tion stage most likely involve actions with an em-phasis on the reward system and inputs from theventral tegmental area and arcuate nucleus of the

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 thetransition from nondependent drug taking to dependent drug taking. Key elements of the reward circuit are dopamine and opioid peptide neurons that intersect atboth the ventral tegmental area and nucleus accumbens and are activated during initial use and the early binge/intoxication stage. Key elements of the stress cir-cuit are CRF and noradrenergic neurons that converge on GABA interneurons in the central nucleus of the amygdala and are activated during the development ofdependence. DA, dopamine; NE, norepinephrine; GABA, �-aminobutyric acid; CRF, corticotropin-releasing factor [Modified with permission from Koob GF, Le MoalM: Neurobiological mechanisms for opponent motivational processes in addiction. Philos Trans R Soc B Biol Sci 2008; 363:3113–3123.]

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hypothalamus. In contrast, the symptoms ofacute withdrawal important for addiction, suchas negative affect and increased anxiety associ-ated with the withdrawal/negative affect stage,most likely involve decreases in function of theextended amygdala system but also a recruitmentof brain stress neurocircuitry therein. The crav-ing stage or preoccupation/anticipation stage in-volves key afferent projections to the nucleus ac-cumbens and amygdala, specifically theprefrontal cortex (for drug-induced reinstate-ment) and the basolateral amygdala (for cue-in-duced reinstatement). Compulsive drug-seekingbehavior is hypothesized to be perpetuated byventral striatal-ventral pallidal-thalamic-corticalloops.

MOLECULAR AND CELLULAR TARGETSWITHIN THE BRAIN CIRCUITSASSOCIATED WITH ADDICTION

The focus of the present review is on the neuro-plasticity of addiction that involves alterations inspecific neurochemical systems in the context of thethree stages of the addiction cycle. However, paral-

lel to the neuroplasticity of the neurocircuitry arethe molecular changes that occur in these samestructures. Chronic exposure to opiates and cocaineleads to activation of cyclic adenosine monophos-phate response-element binding protein (CREB) inthe nucleus accumbens and central nucleus of theamygdala (69, 70). CREB can be phosphorylatedby protein kinase A and by protein kinase regulatedby growth factors, putting it at a point of conver-gence for several intracellular messenger pathwaysthat can regulate gene expression. Activation ofCREB in the nucleus accumbens with psycho-stimulant drugs is linked to the motivational symp-toms of psychostimulant withdrawal, such as dys-phoria, possibly through the induction of theopioid peptide dynorphin, which binds to � opioidreceptors and has been hypothesized to represent amechanism of motivational tolerance and depen-dence (15). Repeated CREB activation drivesdynorphin expression in the nucleus accumbens,which in turn decreases dopaminergic activity andmay activate other brain stress systems, all of whichcan contribute to negative emotional states. Extra-cellular signal-regulated kinase (ERK) is anotherkey element of intracellular signaling that is consid-

Figure 4.

Neurocircuitry schematic illustrating the combination of neuroadaptations in the brain circuitry for the three stages of the addiction cycle that drive drug seekingbehavior in the addicted state. Note the activation of the ventral striatum/dorsal striatum/extended amygdala driven by cues via hippocampal and basolateralamygdala and stress via the insula. The frontal cortex system is compromised, producing deficits in executive function and contributing to the incentive salience ofdrugs compared to natural reinforcers. Dopamine systems are compromised, and brain stress systems such as CRF are activated to reset further the salience ofdrugs and drug-related stimuli in the context of an aversive dysphoric state. AC, anterior cingulate; Acb, nucleus accumbens; AMG, amygdala; BLA, basolateralamygdala; BNST, bed nucleus of the stria terminalis; CRF, corticotropin-releasing factor; DA, dopamine; DGP, dorsal globus pallidus; DS, dorsal striatum; GP, glo-bus pallidus; Hippo, hippocampus; mPFC, medial prefrontal cortex; NE, norepinephrine; OFC, orbitofrontal cortex; SNc, substantia nigra pars compacta; Thal, thala-mus; 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.]

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ered a key component in the plasticity associatedwith repeated administration of cocaine, specifi-cally behavioral sensitization, cocaine reward, andtime-dependent increases in cocaine seeking afterwithdrawal (i.e., incubation effect) (71, 72).

Another molecular target for regulating the plastic-ity that leads to addiction is dysregulation of cystine-glutamate exchange, which is hypothesized to drivepathological glutamate signaling related to severalcomponents of the addiction cycle. Repeated admin-istration of cocaine blunts cystine-glutamate ex-change, leading to reduced basal and increased co-caine-induced glutamate in the nucleus accumbensthat persists for at least 3 weeks after the last cocainetreatment (73). Most compelling is the observationthat treatment with N-acetylcysteine, by activatingcystine-glutamate exchange, prevented cocaine-in-duced escalation and behavioral sensitization, restoredthe ability to induce long-term potentiation and long-term depression in the nucleus accumbens, andblunted reinstatement in animals and conditioned re-activity to drug cues in humans (74–76).

Finally, CREB and other intracellular messen-gers can activate transcription factors, which canchange gene expression and produce long-termchanges in protein expression, and, as a result, neu-ronal function. Although acute administration ofdrugs of abuse can cause rapid (within hours)

activation of members of the Fos protein family,such as c-fos, FosB, Fra-1, and Fra-2 in the nu-cleus accumbens, other transcription factors andisoforms of �FosB (i.e., a highly stable form ofFosB) have been shown to accumulate over lon-ger periods of time (days) with repeated drugadministration (15). Animals with activated�FosB have exaggerated sensitivity to the re-warding effects of drugs of abuse, and �FosB hasbeen hypothesized to act as a sustained molecular“switch” that helps initiate and maintain a stateof addiction (77). Whether (and how) such tran-scription factors influence the function of thebrain stress systems, such as CRF, dynorphin,neuropeptide Y, and the others described above,remains to be further explored.

BRAIN IMAGING CIRCUITS INVOLVED INHUMAN ADDICTION

Brain imaging studies using positron emissiontomography with ligands for measuring oxygenutilization or glucose metabolism or using MRItechniques are providing dramatic insights intothe neurocircuitry changes in the human brainassociated with the development, maintenance,and vulnerability to addiction. These imagingresults overall show a striking resemblance to theneurocircuitry identified by human studies. Dur-ing acute intoxication with alcohol, nicotine,and cocaine, there is an activation of the orbito-frontal cortex, prefrontal cortex, anterior cingu-late, extended amygdala, and ventral striatum.This activation is often accompanied by an in-crease in availability of the neurotransmitter do-pamine. During acute and chronic withdrawal, areversal of these changes occurs, with decreases inmetabolic activity, particularly in the orbitofron-tal cortex, prefrontal cortex, and anterior cingu-late, and decreases in basal dopamine activity asmeasured by decreased D2 receptors in the ven-tral striatum and prefrontal cortex. Cue-inducedreinstatement appears to involve the reactivationof these circuits, much like acute intoxication(78 – 80). Craving or cues associated with co-caine and nicotine activated the prefrontal cortexand anterior cingulate gyrus (81, 82). Imagingstudies also show evidence that cues associatedwith cocaine craving increase dopamine releasein the striatum as well as opioid peptides in theanterior cingulate and frontal cortex (83– 85).Craving in alcoholics appears to be correlatedwith higher opioid peptide activity in the stria-tum but lower dopaminergic activity (86, 87).Thus, imaging studies reveal baseline decreasesin orbitofrontal function and dopamine function

Table 4. Drug CravingDrug craving “Drug craving is the desire for the previously

experienced effects of a psychoactivesubstance. This desire can becomecompelling and can increase in thepresence of both internal and externalcues, particularly with perceivedsubstance availability. It is characterizedby an increased likelihood of drug-seekingbehaviour and, in humans, of drug-relatedthoughts.” (United Nations InternationalDrug Control Programme, 1992)

Craving Type-1 Induced by stimuli that have been pairedwith drug self-administration such asenvironmental cues

Termed conditioned positive reinforcement inexperimental psychology

Animal model: Cue-induced reinstatementwhere a cue previously paired with accessto a drug reinstates responding for a leverthat has been extinguished

Craving Type-2 State of protracted abstinence in drug-dependent individuals weeks after acutewithdrawal.

Conceptualized as a state changecharacterized by anxiety and dysphoria.

Animal model: Residual hypersensitivity tostates of stress and environmentalstressors that lead to relapse to drug-seeking behavior

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during dependence but the reactivation of dopa-mine and reward system function during acutecraving episodes, consistent with the early for-mulation of different neural substrates for crav-ing Type-1 and Type-2 (see above).

SUMMARY AND CONCLUSIONS

Much progress in neurobiology has provided auseful neurocircuitry framework with which toidentify the neurobiological and neuroadaptivemechanisms involved in the development of drugaddiction. The brain reward system implicated inthe development of addiction is composed of keyelements of the basal forebrain with a focus on thenucleus accumbens and central nucleus of theamygdala. Neuropharmacological studies in animalmodels of addiction have provided evidence for theactivation of specific neurochemical mechanisms inspecific brain reward neurochemical systems in thebasal forebrain (dopamine, opioid peptides,GABA, and endocannabinoids) during the binge/intoxication stage. During the withdrawal/negativeaffect stage, dysregulation of the same brain rewardneurochemical systems occurs in the basal forebrain(dopamine, opioid peptides, GABA, and endocan-nabinoids). There is also recruitment of brainstress/aversion systems (CRF and dynorphin) anddysregulation of brain antistress systems (neuro-peptide Y) that contribute to the negative motiva-tional state associated with drug abstinence.During the preoccupation/anticipation stage, neuro-biological circuits that engage the frontal cortexglutamatergic projections to the nucleus accum-bens are critical for drug-induced reinstatement,whereas basolateral amygdala and ventral subicu-lum glutamatergic projections to the nucleus ac-cumbens are involved in cue-induced reinstate-ment. Stress-induced reinstatement appears to bemediated by changes in the antireward systems ofthe extended amygdala. The changes in craving andantireward (stress) systems are hypothesized to re-main outside of a homeostatic state, and as suchconvey the vulnerability for the development of de-pendence and relapse in addiction. Genetic studiesto date in animals suggest roles for the genes encod-ing the neurochemical elements involved in thebrain reward (dopamine, opioid peptide) and stress(neuropeptide Y) systems in the vulnerability toaddiction. Molecular studies have identified trans-duction and transcription factors that may mediatethe dependence-induced reward dysregulation(CREB) and chronic-vulnerability changes(�FosB) in neurocircuitry associated with the de-velopment and maintenance of addiction. Human

imaging studies reveal similar neurocircuits in-volved in acute intoxication, chronic drug depen-dence, and vulnerability to relapse.

Although no exact imaging results necessarilypredict addiction, two salient changes in estab-lished and unrecovered substance-dependent indi-viduals that cut across different drugs are decreasesin orbitofrontal/prefrontal cortex function and de-creases in brain dopamine D2 receptors. No molec-ular markers are sufficiently specific to predict thevulnerability to addiction, but changes in certainintermediate early genes with chronic drug expo-sure in animal models show promise of long-termchanges in specific brain regions that may be com-mon to all drugs of abuse. The continually evolvingknowledge base of the biological and neurobiolog-ical aspects of substance use disorders provides aheuristic framework to better develop diagnoses,prevention, and treatment of substance abuse dis-orders.

A C K N O W L E D G M E N T

Research was supported by National Institutes of Health grants AA06420 andAA08459 from the National Institute on Alcohol Abuse and Alcoholism,DA04043, DA04398, DA10072 and DA023597 from the National Institute onDrug Abuse, and DK26741 from the National Institute of Diabetes and Digestiveand Kidney Diseases. Research also was supported by the Pearson Center forAlcoholism and Addiction Research at The Scripps Research Institute. Theauthor thanks Michael Arends and Mellany Santos for their assistance withmanuscript preparation. This is publication number 21077 from The ScrippsResearch Institute.

KEY POINTS

● The brain reward system implicated in the de-velopment of addiction is composed of keyelements of the basal forebrain that include theventral striatum, the extended amygdala, andits connections.

● Neuropharmacological studies in animalmodels of addiction have provided evidencefor the decreases of specific neurochemicalmechanisms in specific brain reward neuro-chemical systems in the ventral striatum andamygdala (dopamine, opioid peptides, GABA,and endocannabinoids).

● The recruitment of brain stress systems (CRFand norepinephrine) and dysregulation ofbrain anti-stress systems (neuropeptide Y) pro-vide the negative motivational state associatedwith drug abstinence.

● Changes in the reward and stress systems arehypothesized to maintain hedonic stability inan allostatic state (altered reward set point), asopposed to a homeostatic state, and as such

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convey the vulnerability for the developmentof dependence and relapse in addiction.

● Similar neurochemical systems have been im-plicated in animal models of relapse, with do-pamine and opioid peptide systems (and glu-tamate) implicated in drug- and cue-inducedrelapse, possibly more in prefrontal corticaland basolateral amygdala projections to theventral striatum and extended amygdala thanin the reward system itself. The brain stresssystems in the extended amygdala are directlyimplicated in stress-induced relapse.

● Genetic studies in animals using knockouts ofspecific genes suggest roles for the genes en-coding the neurochemical elements involvedin the brain reward (dopamine, opioid pep-tide) and stress (neuropeptide Y) systems in thevulnerability to addiction.

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S U G G E S T E D R E A D I N G

Koob GF: Allostatic view of motivation: implications for psychopathology, inMotivational Factors in the Etiology of Drug Abuse (Nebraska Symposiumon Motivation, vol. 50). Edited by Bevins RA, Bardo MT. Lincoln NE,University of Nebraska Press, 2004, pp 1–18

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Koob GF, Le Moal M: Neurobiology of Addiction. London, Academic Press,2006.

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