Chapter 1. Neurobiology of Addiction

 

CONCEPTUAL FRAMEWORK, DEFINITIONS, AND ANIMAL MODELS

Drug addiction, also known as substance dependence, is a chronic, relapsing disorder characterized by 1) compulsion to seek and take the drug, 2)

loss of control in limiting intake, and 3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is

prevented (defined here as dependence) (Koob and Le Moal 1997). Addiction and substance dependence, as currently defined in DSM-IV-TR

(American Psychiatric Association 2000), will be used interchangeably throughout this chapter and refer to a final stage of a usage process that

moves from drug use to addiction. Clinically, the occasional but limited use of a drug with the potential for abuse or dependence is distinct from

escalated drug use and the emergence of a chronic drug-dependent state. An important goal of current neurobiological research is to understand

the neuropharmacological and neuroadaptive mechanisms within specific neurocircuits that mediate the transition from occasional, controlled drug

use to the loss of behavioral control over drug seeking and drug taking that defines chronic addiction.

Addiction has been conceptualized as a chronic, relapsing disorder with roots in both impulsivity and compulsivity and with neurobiological

mechanisms that change as an individual moves from one domain to the other. Subjects with impulse control disorders experience an increasing

sense of tension or arousal before committing an impulsive act; pleasure, gratification, or relief at the time of committing the act; and, finally,

regret, self-reproach, or guilt following the act. In contrast, individuals with compulsive disorders experience anxiety and stress before committing

a compulsive, repetitive behavior and then relief from the stress by performing the compulsive behavior. In addiction, drug-taking behavior

progresses from impulsivity to compulsivity in a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation.

As individuals move from an impulsive to a compulsive disorder, the drive for the drug-taking behavior shifts from positive to negative

reinforcement (Figures 1–1 and 1–2). Impulsivity and compulsivity can coexist in different stages of the addiction cycle.

TABLE 1–1. Animal models for the motivational component of dependence

Stage of addiction cycle Animal model

Binge/Intoxication Oral drug self-administration

Intravenous drug self-administration

Brain stimulation reward

Place preference

Withdrawal/Negative affect Brain stimulation reward

Place aversion

Anxiogenic-like responses in elevated plus maze

Anxiogenic-like responses in defensive burying

Preoccupation/Anticipation Drug-induced reinstatement

Cue-induced reinstatement

Stress-induced reinstatement

Transition to addiction Drug taking in selected lines of drug-preferring animals

Withdrawal-induced drug taking

Escalation in drug self-administration with prolonged access

Drug taking despite aversive consequences

FIGURE 1–1. Diagram showing 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 (American Psychiatric Association 1994). 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.

Source. Reprinted from Koob GF: “Allostatic View of Motivation: Implications for Psychopathology,” in Motivational Factors in the Etiology of Drug Abuse

(Nebraska Symposium on Motivation, Volume 50). Lincoln, NE, University of Nebraska Press, 2004. Used with permission.Print: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

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FIGURE 1–2. Diagram describing the addiction cycle—preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect—from a

psychiatric perspective with the different criteria for substance dependence incorporated from DSM.

Much of the recent progress in understanding the neurobiology of addiction has derived from the study of animal models of addiction that have

focused on specific drugs such as opiates, psychostimulants, and alcohol (Shippenberg and Koob 2002). Although no animal model of addiction fully

emulates the human condition, animal models do permit investigation of specific elements of the process of drug addiction. Such elements can be

categorized by models of different stages of the addiction cycle. Much of the focus in animal studies has been on the synaptic sites and transductive

mechanisms in the nervous system on which drugs with dependence potential act initially to produce their positive reinforcing effects

(binge/intoxication stage). But components of new animal models that comprise the negative reinforcing effects of dependence

(withdrawal/negative affect stage) and the craving stage (preoccupation/anticipation) have been developed and are beginning to be used to

explore how the nervous system adapts to drug use (Shippenberg and Koob 2002) (Table 1–1). The neurobiological mechanisms of addiction

involved in various stages of the addiction cycle have a specific focus on certain brain circuits and the molecular/neurochemical changes associated

with those circuits during the transition from drug taking to drug addiction and how those changes persist in the vulnerability to relapse (Koob and

Le Moal 2001).

Research was supported by National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA04043 and

DA04398 from National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research was also

supported by the Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute. The author would like to thank Mike Arends for his

assistance with manuscript preparation. This is publication number 18781 from The Scripps Research Institute.

NEUROBIOLOGICAL MECHANISMS OF THE BINGE/INTOXICATION STAGE

It has long been hypothesized that a key element of drug addiction is that drugs of abuse activate brain reward systems and that understanding the

neurobiological bases for acute drug reward is vital to understanding how these systems change during the development of addiction (Koob 2004;

Koob and Le Moal 1997). Research on the neurobiology of the positive reinforcing effects of drugs with addiction potential has focused principally

on the origins and terminal areas of the mesocorticolimbic dopamine system. Indeed, there is compelling evidence indicating the importance of this

system in psychostimulant reward. However, study of the specific circuitry associated with drug reward has been broadened to include the many

neural inputs and outputs that interact with the basal forebrain. More recently, research on specific components of the basal forebrain that have

been identified as associated with drug reward has focused on both the nucleus accumbens and amygdala (Koob and Le Moal 2001; Koob et al.

1998) (see Figure 1–3). As our understanding about the neural circuits involved in the reinforcing effects of drugs with dependence potential has

evolved, so too has our understanding of the role of neurotransmitters/neuromodulators. Five of those systems have been identified as having a

role in the acute reinforcing effects: dopamine, opioid peptides, -aminobutyric acid (GABA), serotonin, and endocannabinoids (Table 1–2).

FIGURE 1–3. Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acute

reinforcing actions of drugs of abuse.Print: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

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Cocaine and amphetamines activate the release of dopamine in the nucleus accumbens and amygdala via direct actions on dopamine terminals. Opioids activate

opioid receptors in the ventral tegmental area, nucleus accumbens, and amygdala via direct actions on interneurons. Opioids facilitate the release of dopamine in

the nucleus accumbens via an action either in the ventral tegmental area or the nucleus accumbens, but are also hypothesized to activate elements independent

of the dopamine system. Alcohol activates -aminobutyric acidA (GABAA) receptors in the ventral tegmental area, nucleus accumbens, and amygdala via either

direct actions at the GABAA receptor or through indirect release of GABA. Alcohol is hypothesized to facilitate the release of opioid peptides in the ventral

tegmental area, nucleus accumbens, and central nucleus of the amygdala. Alcohol facilitates the release of dopamine in the nucleus accumbens via an action

either in the ventral tegmental area or the nucleus accumbens. Nicotine activates nicotinic acetylcholine receptors in the ventral tegmental area, nucleus

accumbens, and amygdala, either directly or indirectly, via actions on interneurons. Nicotine may also activate opioid peptide release in the nucleus accumbens or

amygdala, independent of the dopamine system. Cannabinoids activate cannabinoid type 1 (CB 1) receptors in the ventral tegmental area, nucleus accumbens,

and amygdala via direct actions on interneurons. Cannabinoids facilitate the release of dopamine in the nucleus accumbens via an action either in the ventral

tegmental area or the nucleus accumbens, but are also hypothesized to activate elements independent of the dopamine system. Endogenous cannabinoids may

interact with postsynaptic elements in the nucleus accumbens involving dopamine and/or opioid peptide systems. The blue arrows represent the interactions

within the extended amygdala system hypothesized to have a key role in psychostimulant reinforcement. AC = anterior commissure; AMG = amygdala; ARC =

arcuate nucleus; BNST = bed nucleus of the stria terminalis; Cer = cerebellum; C-P = caudate-putamen; DMT = dorsomedial thalamus; FC = frontal cortex;

Hippo = hippocampus; IF = inferior colliculus; LC = locus coeruleus; LH = lateral hypothalamus; N Acc = nucleus accumbens; OT = olfactory tract; PAG =

periaqueductal gray; RPn = reticular pontine nucleus; SC = superior colliculus; SNr = substantia nigra pars reticulata; VP = ventral pallidum; VTA = ventral

tegmental area.

Source. Reprinted from Koob GF: “The Neurocircuitry of Addiction: Implications for Treatment.” Clinical Neuroscience Research 5:89–101, 2005. Used with

permission.

TABLE 1–2. Neurobiological substrates for the acute reinforcing effects of drugs of abuse

Drug of abuse Neurotransmitter Site

Cocaine and amphetamines Dopamine Nucleus accumbens

-Aminobutyric acid Amygdala

Opioids Opioid peptides Nucleus accumbens

Dopamine Ventral tegmental area

Endocannabinoids

Nicotine Dopamine Nucleus accumbens

-Aminobutyric acid Ventral tegmental area

Opioid peptides Amygdala

9 -Tetrahydrocannabinol

Endocannabinoids Nucleus accumbens

Opioid peptides Ventral tegmental area

Dopamine

Alcohol Dopamine Nucleus accumbens

Opioid peptides Ventral tegmental areaPrint: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

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Drug of abuse Neurotransmitter Site

-Aminobutyric acid Amygdala

Glutamate

Endocannabinoids

The mesolimbic dopamine system is well established as having a critical role in the activating and reinforcing effects of indirect sympathomimetics

such as cocaine, methamphetamine, and nicotine. However, although all drugs of abuse acutely activate the mesolimbic dopamine system,

particularly in the medial shell region of the nucleus accumbens, the role of dopamine becomes less critical with opioid drugs, alcohol, and

9 -tetrahydrocannabinol ( 9 -THC). Here, other neurotransmitter systems such as opioid peptides, GABA, and endocannabinoids may play key roles

either in series or independent of activation of the mesolimbic dopamine system. For example, a particularly sensitive site for blockade of the acute

reinforcing effects of alcohol with opioid and GABAergic antagonists appears to be the central nucleus of the amygdala (Koob 2003). Opioid peptide

antagonists also block the reinforcing effects of 9 -THC, a key active ingredient in marijuana.

Serotonin receptors at specific subtypes modulate psychostimulant and alcohol reward. Moreover, endocannabinoid mechanisms have been

implicated in psychostimulant, opioid, alcohol, and cannabinoid reward. For example, serotonin type 1B (5-HT1B) receptor agonists facilitate cocaine

reward (Parsons et al. 1998) and decrease alcohol reward (Tomkins and O’Neill 2000). Cannabinoid type 1 (CB1) antagonists block opioid, alcohol,

and cannabinoid reward (Justinova et al. 2004, 2005). In summary, multiple neurotransmitters are implicated in the acute reinforcing effects of

drugs of abuse. Key players in the nucleus accumbens and amygdala are dopamine, opioid peptide, and GABA systems with modulation via

serotonin and endocannabinoids.

NEUROBIOLOGICAL MECHANISMS OF THE WITHDRAWAL/NEGATIVE AFFECT STAGE

The neural substrates and neuropharmacological mechanisms for the negative motivational effects of drug withdrawal may involve disruption of the

same neural systems implicated in the positive reinforcing effects of drugs but also involve recruitment of anti-reward systems. Measures of brain

reward function during acute abstinence from all major drugs with dependence potential have revealed increases in brain reward thresholds as

measured by direct brain-stimulation reward (Epping-Jordan et al. 1998; Gardner and Vorel 1998; Markou and Koob 1991; Paterson et al. 2000;

Schulteis et al. 1994, 1995). These increases in reward thresholds may reflect decreases in the activity of reward neurotransmitter systems in the

midbrain and forebrain implicated in the positive reinforcing effects of drugs.

Changes at the neurochemical level that reflect changes in the neurotransmitter system implicated in acute drug reward are called within-system

neuroadaptations to chronic drug exposure. These neuroadaptations include decreases in dopaminergic and serotonergic transmission in the

nucleus accumbens during drug withdrawal as measured by in vivo microdialysis (Parsons and Justice 1993; Weiss et al. 1992), increased

sensitivity of opioid receptor transduction mechanisms in the nucleus accumbens during opioid withdrawal (Stinus et al. 1990), decreased

GABAergic and increased N-methyl-D-aspartate (NMDA) glutamatergic transmission during alcohol withdrawal (Davidson et al. 1995; Morrisett

1994; Roberts et al. 1996; Weiss et al. 1996), and differential regional changes in nicotinic receptor function (Collins et al. 1990; Dani and

Heinemann 1996).

It is hypothesized that decreases in reward neurotransmitters reflect a within-system neuroadaptation and contribute significantly to the negative

motivational state associated with acute drug abstinence. In a within-system neuroadaptation, “the primary cellular response element to the drug

would itself adapt to neutralize the drug’s effects; persistence of the opposing effects after the drug disappears would produce the withdrawal

response” (Koob and Bloom 1988, p. 720). The decreased reward system function may persist in the form of long-term biochemical changes that

contribute to the clinical syndrome of protracted abstinence and vulnerability to relapse.

The emotional dysregulation associated with the withdrawal/negative affect stage may also involve a between system neuroadaptation, in which

neurochemical systems other than those involved in positive rewarding effects of drugs of abuse are recruited or dysregulated by chronic activation

of the reward system (Koob and Bloom 1988). In addition, brain neurochemical systems involved in stress modulation may be engaged within the

neurocircuitry of the brain stress systems in an attempt to overcome the chronic presence of the perturbing drug and to restore normal function

despite the drug’s presence. Both the hypothalamic-pituitary-adrenal axis and the brain stress system mediated by corticotropin-releasing factor

(CRF) are dysregulated by chronic administration of all major drugs with dependence or abuse potential, resulting in the common response of

elevated adrenocorticotropic hormone, corticosterone, and amygdala CRF during acute withdrawal (Delfs et al. 2000; Koob et al. 1994; Merlo-Pich et

1. 1995; Olive et al. 2002; Rasmussen et al. 2000; Rivier et al. 1984). Acute withdrawal from drugs may also increase the release of norepinephrine

in the bed nucleus of the stria terminalis (BNST) and decrease levels of neuropeptide Y (NPY) in the central and medial nuclei of the amygdala (Roy

and Pandey 2002).

During the development of dependence, these results suggest not only a change in the function of neurotransmitters associated with the acute

reinforcing effects of drugs (dopamine, opioid peptides, serotonin, GABA, and endocannabinoids) but also recruitment of the brain stress system

(CRF and norepinephrine) and dysregulation of the NPY brain anti-stress system (Koob and Le Moal 2001) (Table 1–3). Moreover, activation of the

brain stress systems may not only contribute to the negative motivational state associated with acute abstinence but may also contribute to the

vulnerability to stressors observed during protracted abstinence in humans.

TABLE 1–3. Neurotransmitters implicated in the motivational effects of withdrawal from drugs of abuse

Neurotransmitter

Functional effect

Dopamine

Dysphoria

Serotonin

Dysphoria

-Aminobutyric acid

Anxiety, panic attacks

Neuropeptide Y

Anti-stress

Dynorphin

Dysphoria

Norepinephrine

Stress

Corticotropin-releasing factor

Stress

The neuroanatomical entity termed the extended amygdala (Heimer and Alheid 1991) may represent a common anatomical substrate for acute drug

reward and a common neuroanatomical substrate for the negative effects on reward function produced by stress that help drive compulsive drug

administration. The extended amygdala is composed of the BNST, the central nucleus of the amygdala, and a transition zone in the medial subregion

of the nucleus accumbens (shell of the nucleus accumbens). Each of these regions has cytoarchitectural and circuitry similarities (Heimer and Alheid

1991). The extended amygdala receives numerous afferents from limbic structures such as the basolateral amygdala and hippocampus and sends

efferents to the medial part of the ventral pallidum and a large projection to the lateral hypothalamus. Thus, the specific brain areas that link

classical limbic (emotional) structures with the extrapyramidal motor system are further defined (Alheid et al. 1995).

The concept of an anti-reward system has been recently formulated to accommodate the significant changes in brain emotional systems associated

with the development of dependence (Koob and Le Moal 2005). The anti-reward concept is based on the hypothesis that there are brain systems in

place to limit reward (Koob and Bloom 1988), an opponent-process concept that forms a general feature of biological systems. The concept of anPrint: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

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anti-reward system is derived from the hypothesis that between-system neuroadaptations result from activation of the reward system at the

neurocircuitry level. A between-system neuroadaptation is a circuitry change in which circuit B (anti-reward circuit) is activated by circuit A (reward

circuit). This concept has its origins in the theoretical pharmacology that predates opponent-process theory (Martin 1967). Thus, the activation of

brain stress systems such as CRF, norepinephrine, and dynorphin with concomitant dysregulation of the NPY system may represent the recruitment

of an anti-reward system in the extended amygdala that produces the motivational components of drug withdrawal and provides a baseline hedonic

shift that facilitates craving mechanisms (Koob and Le Moal 2005).

NEUROBIOLOGICAL MECHANISMS OF THE PREOCCUPATION/ANTICIPATION STAGE

The preoccupation/anticipation stage of the addiction cycle has long been hypothesized to be a key element of relapse in humans, and it contributes

to the definition of addiction as a chronic, relapsing disorder. Although often linked to the construct of craving, craving per se has been difficult to

measure in human clinical studies (Tiffany et al. 2000) and often does not correlate with relapse. Nevertheless, the stage of the addiction cycle

when the individual reinstates drug-seeking behavior after abstinence remains a challenge for researchers who focus on neurobiological

mechanisms and medication development for treatment.

Animal models of craving can be divided into two domains: craving type 1 involves drug seeking induced by stimuli paired with drug taking; craving

type 2 features drug seeking induced by an acute stressor or a state of stress (Table 1–4). Craving type 1 animal models emphasize the use of

drug-primed reinstatement and cue-induced reinstatement. Craving type 2 animal models are characterized by stress-induced reinstatement in

animals that have acquired drug self-administration and then have been subjected to extinction of responding for the drug.

TABLE 1–4. Drug craving

Drug

craving

“Drug craving is the desire for the previously experienced effects of a psychoactive substance. This desire can become compelling and can increase in

the presence of both internal and external cues, particularly with perceived substance availability. It is characterised by an increased likelihood of

drug-seeking behaviour or, in humans, drug-related thoughts.” (United Nations International Drug Control Programme and World Health Organization

1992)

Craving

type 1

Induced by stimuli that have been paired with drug self-administration, such as environmental cues.

Termed conditioned positive reinforcement in experimental psychology.

Animal model: cue-induced reinstatement in which a cue previously paired with access to a drug reinstates responding for a lever that has been

extinguished.

Craving

type 2

State of protracted abstinence in drug-dependent individuals, weeks after acute withdrawal.

Conceptualized as a state change, characterized by anxiety and dysphoria.

Animal model: residual hypersensitivity to states of stress and environmental stressors that lead to relapse to drug-seeking behavior.

Most evidence from animal studies suggests that drug-induced reinstatement is localized to the medial prefrontal cortex/nucleus

accumbens/ventral pallidum circuit mediated by the neurotransmitter glutamate (McFarland and Kalivas 2001). In contrast, neuropharmacological

and neurobiological studies using animal models for cue-induced reinstatement include the basolateral amygdala as a critical substrate, with a

possible feed-forward mechanism through the prefrontal cortex system involved in drug-induced reinstatement (Everitt and Wolf 2002; Weiss et al.

2001). Neurotransmitter systems involved in drug-induced reinstatement are characterized by a glutamatergic projection from the frontal cortex to

the nucleus accumbens that is modulated by dopamine activity in the frontal cortex. Cue-induced reinstatement involves dopamine modulation in

the basolateral amygdala and a glutamatergic projection to the nucleus accumbens from both the basolateral amygdala and ventral subiculum

(Everitt and Wolf 2002; Vorel et al. 2001). In contrast, stress-induced reinstatement of drug-related responding in animal models appears to

depend on the activation of both CRF and norepinephrine in elements of the extended amygdala (central nucleus of the amygdala and BNST)

(Shaham et al. 2003; Shalev et al. 2002). Protracted abstinence, largely described in alcohol dependence models, appears to involve overactive

glutamatergic and CRF systems (De Witte et al. 2005; Valdez et al. 2002).

OVERALL NEUROCIRCUITRY OF ADDICTION

In summary, three neurobiological circuits have been identified that have heuristic value for the study of the neurobiological changes associated

with the development and persistence of drug dependence (Figure 1–4). The acute reinforcing effects of drugs of abuse that make up the

binge/intoxication stage most likely involve actions with an emphasis on the extended amygdala reward system and inputs from the ventral

tegmental area and arcuate nucleus of the hypothalamus. In contrast, the symptoms of acute withdrawal that are important in addiction, such as

negative affect and increased anxiety associated with the withdrawal/negative affect stage, most likely include decreases in function of the

extended amygdala reward system but also a recruitment of brain stress neurocircuitry. The craving stage, or preoccupation/anticipation stage,

features key afferent projections to the extended amygdala and nucleus accumbens, specifically the prefrontal cortex (for drug-induced

reinstatement) and the basolateral amygdala (for cue-induced reinstatement). Compulsive drug-seeking behavior is thought to be driven by ventral

striatal–ventral pallidal–thalamic-cortical loops.

FIGURE 1–4. Key common neurocircuitry elements in drug-seeking behavior of addiction.Print: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

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Three major circuits that underlie addiction can be distilled from the literature. A drug reinforcement circuit ( reward and stress) is composed of the extended

amygdala, including the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the transition zone in the shell of the nucleus accumbens.

Multiple modulator neurotransmitters are hypothesized, including dopamine and opioid peptides for reward; and corticotropin-releasing factor and norepinephrine

for stress. The extended amygdala is hypothesized to mediate integration of rewarding stimuli or stimuli with positive incentive salience and aversive stimuli or

stimuli with negative aversive salience. During acute intoxication, valence is weighted on processing rewarding stimuli, and, during the development of

dependence, aversive stimuli come to dominate function. A drug- and cue-induced reinstatement ( craving) neurocircuit is composed of the prefrontal (anterior

cingulate, prelimbic, orbitofrontal) cortex and basolateral amygdala, with a primary role hypothesized for the basolateral amygdala in cue-induced craving and a

primary role for the medial prefrontal cortex in drug-induced craving, based on animal studies. Human imaging studies have shown an important role for the

orbitofrontal cortex in craving (see text). A drug-seeking circuit ( compulsive) circuit is composed of the nucleus accumbens, ventral pallidum, thalamus, and

orbitofrontal cortex. The nucleus accumbens has long been hypothesized to have a role in translating motivation to action and forms an interface between the

reward functions of the extended amygdala and the motor functions of the ventral striatal–ventral pallidal–thalamic-cortical loops. The striatal-pallidal-thalamic

loops reciprocally move from prefrontal cortex to orbitofrontal cortex to motor cortex—ultimately leading to drug-seeking behavior. Note that, for the sake of

simplicity, other structures are not included, such as the hippocampus (which presumably mediates context-specific learning, including that associated with drug

actions). Also note that dopamine and norepinephrine both have widespread innervation of cortical regions and may modulate function relevant to drug addiction

in those structures. CRF = corticotropin-releasing factor; DA = dopamine; -END = -endorphin; ENK = emkephalin; NE = norepinephrine; VTA = ventral

tegmental area.

Source. Reprinted from Koob GF, Le Moal M: Neurobiology of Addiction. London, Academic Press, 2005. Used with permission.

MOLECULAR AND CELLULAR MECHANISMS IN THE BRAIN CIRCUITS ASSOCIATED WITH ADDICTION

Determining which genetic and environmental factors produce the vulnerability to addiction has become one of the most exciting pursuits in the

study of the neurobiology of addiction. One hypothesis is that molecular changes at the gene or gene transcription level will provide the key to

understanding such vulnerability. The search at the molecular level has led to an examination of how repeated perturbation of intracellular signal

transduction pathways leads to changes in nuclear function and altered rates of transcription of particular target genes. Altered expression of such

genes would lead to altered activity of the neurons where such changes occur and, ultimately, to changes in the function of neural circuits in which

those neurons operate.

Two transcription factors in particular have been implicated in the plasticity associated with addiction: cyclic adenosine monophosphate (cAMP)

response element-binding protein (CREB), and FosB. CREB regulates the transcription of genes that contain a cAMP response element site within

the regulatory regions and can be found ubiquitously in genes expressed in the central nervous system such as those that encode neuropeptides,

synthetic enzymes for neurotransmitters, signaling proteins, and other transcription factors. CREB can be phosphorylated by protein kinase A and

by protein kinases regulated by growth factors, putting it at a point of convergence for several intracellular messenger pathways that can regulate

the expression of genes.

Much work in the addiction field has shown that activation of CREB in the nucleus accumbens is a consequence of chronic exposure to opiates,

cocaine, and alcohol, and deactivation of CREB in the central nucleus of the amygdala with alcohol and nicotine. The activation of CREB is linked to

the activation of the dysphoria-inducing opioid receptor that binds the opioid peptide dynorphin. Up-regulation of the cAMP pathway and CREB in

the nucleus accumbens is thus believed to represent a mechanism of motivational tolerance and dependence. More specifically, these molecular

adaptations may decrease an individual’s sensitivity to the rewarding effects of subsequent drug exposures (tolerance) and impair the reward

pathway (dependence) so that after removal of the drug the individual is left in an amotivational, dysphoric, or depressed-like state (Nestler 2004).

In contrast, decreased CREB phosphorylation has been observed in the central nucleus of the amygdala during alcohol withdrawal and has been

linked to decreased NPY function and, consequently, the increased anxiety-like responses associated with acute alcohol withdrawal (Pandey 2004).

Increased CREB in the nucleus accumbens and decreased CREB in the central nucleus of the amygdala are not necessarily mutually exclusive.

Furthermore, these effects point to transduction mechanisms that could produce neurochemical changes in the neurocircuits outlined above as

being important for breaks with reward homeostasis in addiction.

The molecular changes associated with long-term changes in brain function as a result of chronic exposure to drugs of abuse have also been linked

to changes in transcription factors, which can change gene expression and produce long-term changes in protein expression and, as a result,

neuronal function. Although acute administration of drugs of abuse can cause a rapid (hours) activation of members of the Fos family, such as c-fos,

FosB, Fra-1, and Fra-2, in the nucleus accumbens, other transcription factors, isoforms of FosB, accumulate over longer periods of time (days) with

repeated drug administration (Nestler 2004). Animals with activated FosB have exaggerated sensitivity to the rewarding effects of drugs of abuse.

Therefore, FosB may be a sustained molecular trigger that helps to initiate and maintain a state of addiction. How changes in FosB that can last

for days can also translate into vulnerability to relapse remains a challenge for future work (Nestler 2004).

Genetic and molecular-genetic animal models have provided a molecular basis to support the neuropharmacological substrates identified in

neurocircuitry studies. Alcohol-preferring rats have been bred that show particularly high levels of voluntary consumption of alcohol, increasedPrint: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

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anxiety-like responses, and numerous neuropharmacological phenotypes, such as decreased dopaminergic activity and decreased NPY activity

(McBride et al. 1990; Murphy et al. 2002). In an alcohol-preferring and -nonpreferring cross, a quantitative trait locus was identified on

chromosome 4, a region on which the gene for NPY has been mapped. In the inbred preferring- and nonpreferring-quantitative trait loci analyses,

loci on chromosomes 3, 4, and 8 have been identified that correspond to loci near the genes for the dopamine D2 and serotonin 5-HT1B receptors

(Carr et al. 1998).

Advances in molecular biology have given researchers the ability to systematically inactivate genes that control the expression of proteins that

make up receptors or neurotransmitters/neuromodulators in the central nervous system using the gene knockout approach. “Knockout” mice have

a gene inactivated by homologous recombination. A knockout mouse deficient in both alleles of a gene is homozygous for the deletion and is termed

a null mutation (–/–). A mouse that is deficient in only one of the two alleles for the gene is termed a heterozygote (+/–). Transgenic knockin mice

have an extra gene introduced into their germline. An additional copy of a normal gene is inserted into the genome of the mouse to examine the

overexpression effects of the product of that gene. Alternatively, a new gene, not normally found in the mouse, can be added, such as a gene

associated with a specific pathology in humans. Wild-type controls are animals bred through the same breeding strategies involving mice that

receive the transgene injected into the fertilized egg (transgenics) or a targeted gene construct injected into the genome via embryonic stem cells

(knockout) but lacking the mutation on either allele of the gene in question. Although such an approach does not guarantee that these genes are

the vulnerable ones in the human population, the genes do provide viable candidates for exploring the genetic basis of endophenotypes associated

with addiction (Koob et al. 2001).

Notable positive results with gene knockout studies in mice have focused on knockout of the opioid receptor, which eliminates opioid, nicotine,

and cannabinoid reward and alcohol drinking in mice (Contet et al. 2004). Opioid (morphine) reinforcement as measured by conditioned place

preference or self-administration is absent in knockout mice, and there is no development of somatic signs of dependence to morphine in these

mice. Indeed, to date, all morphine effects tested, including analgesia, hyperlocomotion, respiratory depression, and inhibition of gastrointestinal

transit, are abolished in knockout mice (Gaveriaux-Ruff and Kieffer 2002).

Selective deletion of the genes for expression of different dopamine receptor subtypes and the dopamine transporter has revealed significant

effects to challenges with psychomotor stimulants. D1 receptor knockout mice show no response to D1 agonists or antagonists and show a blunted

response to the locomotor-activating effects of cocaine and amphetamine. When compared with wild-type mice, D1 knockout mice are also impaired

in their acquisition of intravenous cocaine self-administration (Caine et al. 2007). D2 knockout mice have severe motor deficits and blunted

psychostimulant responses to psychostimulants and opiates, but the effects on psychostimulant reward are less consistent. Dopamine transporter

knockout mice are dramatically hyperactive but also show a blunted response to psychostimulants. Although developmental factors must be taken

into account for the compensatory effect of deleting any one or a combination of genes, it is clear that D1 and D2 receptors and the dopamine

transporter play important roles in the actions of psychomotor stimulants (Caine et al. 2002, 2007).

BRAIN IMAGING CIRCUITS INVOLVED IN HUMAN ADDICTION

Brain imaging studies using magnetic resonance imaging techniques or positron emission tomography with ligands for measuring oxygen utilization

or glucose metabolism are providing dramatic insights into the neurocircuitry changes in the human brain associated with the development of,

maintenance of, and vulnerability to addiction. Overall, these imaging results show a striking resemblance to the neurocircuitry identified in studies

in animals. During acute intoxication with alcohol, nicotine, or cocaine, there is an activation of the orbitofrontal cortex, prefrontal cortex, anterior

cingulate, extended amygdala, and ventral striatum. This activation is often accompanied by an increase in availability of the neurotransmitter

dopamine. During acute and chronic withdrawal there is a reversal of these changes accompanied by decreases in metabolic activity, particularly in

the orbitofrontal cortex, prefrontal cortex, and anterior cingulate, and decreases in basal dopamine activity as measured by decreased D2 receptors

in the ventral striatum and prefrontal cortex. Cue-induced reinstatement appears to involve a reactivation of these circuits, much like that of acute

intoxication (Bonson et al. 2002; Breiter et al. 2001; Childress et al. 1999). Craving or cues associated with cocaine and nicotine produce activation

of the prefrontal cortex and anterior cingulate gyrus (Lee et al. 2005; Risinger et al. 2005). Imaging studies also show evidence that cues

associated with cocaine craving increase dopamine release in the striatum as well as opioid peptides in the anterior cingulate and frontal cortex

(Gorelick et al. 2005; Volkow et al. 2006; Wong et al. 2006). Craving in alcoholic individuals appears to be correlated with higher opioid peptide

activity in the striatum but lower dopaminergic activity (Heinz et al. 2004, 2005). Thus, imaging studies to date reveal baseline decreases in

orbitofrontal function and dopamine function during dependence, but a reactivation of the dopamine and reward system function during acute

craving episodes consistent with the early formulation of different neural substrates for craving type 1 and type 2 (see above).

CONCLUSION

Much progress in neurobiology has provided a useful neurocircuitry framework with which to identify the neurobiological and neuroadaptive

mechanisms involved in the development of drug addiction. The brain reward system implicated in the development of addiction is composed of key

elements of the basal forebrain, with the nucleus accumbens and central nucleus of the amygdala playing particularly important roles.

Neuropharmacological studies in animal models of addiction have provided evidence that indicates the activation of specific neurochemical

mechanisms in specific brain reward neurochemical systems in the basal forebrain (dopamine, opioid peptides, GABA, serotonin, and

endocannabinoids) during the binge/intoxication stage. During the withdrawal/negative affect stage, there is a dysregulation of the same brain

reward neurochemical systems in the basal forebrain. There is also recruitment of brain stress systems (CRF and norepinephrine) and dysregulation

of brain anti-stress systems (NPY) that contribute to the negative motivational state associated with drug abstinence. During the

preoccupation/anticipation stage, neurobiological circuits that engage the frontal cortex glutamatergic projections to the nucleus accumbens are

critical for drug-induced reinstatement, whereas basolateral amygdala and ventral subiculum glutamatergic projections to the nucleus accumbens

are involved in cue-induced reinstatement. Stress-induced reinstatement appears to be mediated by changes in the anti-reward systems of the

extended amygdala. The changes in craving and anti-reward (stress) systems are hypothesized to remain outside of a homeostatic state. As such,

these changes convey the vulnerability for development of dependence and relapse in addiction. To date, genetic studies in animals suggest roles

for the genes encoding the neurochemical elements involved in the brain reward (dopamine, opioid peptide) and stress (NPY) systems in the

vulnerability to addiction. Molecular studies have identified transduction and transcription factors that may mediate the dependence-induced

reward dysregulation (CREB) and chronic-vulnerability changes ( FosB) in neurocircuitry associated with the development and maintenance of

addiction. Human imaging studies reveal similar neurocircuits involved in acute intoxication, chronic drug dependence, and vulnerability to relapse.

Although no exact imaging results necessarily predict addiction, two salient changes in established and unrecovered substance-dependent

individuals that cut across different drugs are decreases in orbitofrontal/prefrontal cortex function and in brain D2 receptors. No molecular markers

are sufficiently specific to predict vulnerability to addiction, but changes in certain intermediate early genes with chronic drug exposure in animal

models show promise of long-term changes in specific brain regions that may be common to all drugs of abuse. The continually evolving knowledge

base of biological and neurobiological aspects of substance use disorders provides a heuristic framework to better develop the diagnoses,

prevention, and treatment of substance abuse disorders.

KEY POINTS

The brain reward system implicated in the development of addiction comprises key elements of the basal forebrain such as the ventral striatum, the extended

amygdala, and its connections.

Neuropharmacological studies in animal models of addiction have provided evidence to indicate that there are decreases of specific neurochemical mechanisms

in specific brain reward neurochemical systems in the ventral striatum and amygdala (dopamine, opioid peptides,

-aminobutyric acid, and endocannabinoids;

light side of addiction).Print: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

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Recruitment of brain stress systems (corticotropin-releasing factor and norepinephrine; dark side of addiction) and dysregulation of brain anti-stress systems

(neuropeptide Y) provide the negative motivational state associated with drug abstinence.

Changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state (altered reward set point), as opposed to a

homeostatic state and, as such, convey the vulnerability for the development of dependence and relapse in addiction.

Similar neurochemical systems have been implicated in animal models of relapse, with dopamine and opioid peptide systems (and glutamate) being implicated

in drug- and cue-induced relapse, possibly more in prefrontal cortical and basolateral amygdala projections to the ventral striatum and extended amygdala than in

the reward system itself. The brain stress systems in the extended amygdala are directly implicated in stress-induced relapse.

Genetic studies to date in animals using knockouts of specific genes suggest roles for the genes encoding the neurochemical elements involved in the brain

reward (dopamine, opioid peptide) and stress (neuropeptide Y) systems in the vulnerability to addiction.

REFERENCES

Alheid GF, De Olmos JS, Beltramino CA: Amygdala and extended amygdala, in The Rat Nervous System. Edited by Paxinos G. San Diego, CA,

Academic Press, 1995, pp 495–578

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric

Association, 1994

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American

Psychiatric Association, 2000

Bonson KR, Grant SJ, Contoreggi CS, et al: Neural systems and cue-induced cocaine craving. Neuropsychopharmacology 26:376–386, 2002

[PubMed]

Breiter HC, Aharon I, Kahneman D, et al: Functional imaging of neural responses to expectancy and experience of monetary gains and losses.

Neuron 30:619–639, 2001 [PubMed]

Caine SB, Negus SS, Mello NK, et al: Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and

novel D2 receptor antagonists. J Neurosci 22:2977–2988, 2002 [PubMed]

Caine SB, Thomsen M, Gabriel KI, et al: Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice. J Neurosci 27:13140–13150,

2007 [PubMed]

Carr LG, Foroud T, Bice P, et al: A quantitative trait locus for alcohol consumption in selectively bred rat lines. Alcohol Clin Exp Res 22:884–887,

1998 [PubMed]

Childress AR, Mozley PD, McElgin W, et al: Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18, 1999 [Full Text]

[PubMed]

Collins AC, Bhat RV, Pauly JR, et al: Modulation of nicotine receptors by chronic exposure to nicotinic agonists and antagonists, in The Biology of

Nicotine Dependence (Ciba Foundation Symposium, Vol 152). Edited by Bock G, Marsh J. New York, Wiley, 1990, pp 87–105

Contet C, Kieffer BL, Befort K: Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol 14:370–378, 2004 [PubMed]

Dani JA, Heinemann S: Molecular and cellular aspects of nicotine abuse. Neuron 16:905–908, 1996 [PubMed]

Davidson M, Shanley B, Wilce P: Increased NMDA-induced excitability during ethanol withdrawal: a behavioural and histological study. Brain Res

674:91–96, 1995 [PubMed]

Delfs JM, Zhu Y, Druhan JP, et al: Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature 403:430–434,

2000 [PubMed]

De Witte P, Littleton J, Parot P, et al: Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS

Drugs 19:517–537, 2005

Epping-Jordan MP, Watkins SS, Koob GF, et al: Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76–79, 1998

[PubMed]

Everitt BJ, Wolf ME: Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320, 2002; erratum in J Neurosci 22:1a,

2002

Gardner EL, Vorel SR: Cannabinoid transmission and reward-related events. Neurobiol Dis 5:502–533, 1998 [PubMed]

Gaveriaux-Ruff C, Kieffer BL: Opioid receptor genes inactivated in mice: the highlights. Neuropeptides 36:62–71, 2002 [PubMed]

Gorelick DA, Kim YK, Bencherif B, et al: Imaging brain mu-opioid receptors in abstinent cocaine users: time course and relation to cocaine craving.

Biol Psychiatry 57:1573–1582, 2005 [PubMed]

Heimer L, Alheid G: Piecing together the puzzle of basal forebrain anatomy, in The Basal Forebrain: Anatomy to Function (Advances in Experimental

Medicine and Biology, Vol 295). Edited by Napier TC, Kalivas PW, Hanin I. New York, Plenum, 1991, pp 1–42

Heinz A, Siessmeier T, Wrase J, et al: Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues

and craving. Am J Psychiatry 161:1783–1789, 2004; erratum in Am J Psychiatry 161:2344, 2004

Heinz A, Reimold M, Wrase J, et al: Correlation of stable elevations in striatal mu-opioid receptor availability in detoxified alcoholic patients with

alcohol craving: a positron emission tomography study using carbon 11-labeled carfentanil. Arch Gen Psychiatry 62:57–64, 2005; erratum in Arch

Gen Psychiatry 62:983, 2005

Justinova Z, Tanda G, Munzar P, et al: The opioid antagonist naltrexone reduces the reinforcing effects of delta 9 tetrahydrocannabinol (THC) in

squirrel monkeys. Psychopharmacology (Berl) 173:186–194, 2004 [PubMed]

Justinova Z, Solinas M, Tanda G, et al: The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously

self-administered by squirrel monkeys. J Neurosci 25:5645–5650, 2005 [PubMed]

Koob GF: Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27:232–243, 2003 [PubMed]

Koob GF: Allostatic view of motivation: implications for psychopathology, in Motivational Factors in the Etiology of Drug Abuse (Nebraska

Symposium on Motivation, Vol 50). Lincoln, University of Nebraska Press, 2004, pp 1–18

Koob GF: The neurocircuitry of addiction: implications for treatment. Clin Neurosci Res 5:89–101, 2005

Koob GF, Bloom FE: Cellular and molecular mechanisms of drug dependence. Science 242:715–723, 1988 [PubMed]

Koob GF, Le Moal M: Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58, 1997 [PubMed]Print: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

9 of 10

18/10/2008 10:03

Koob GF, Le Moal M: Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129, 2001 [PubMed]

Koob GF, Le Moal M: Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci 8:1442–1444, 2005 [PubMed]

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

Koob GF, Heinrichs SC, Menzaghi F, et al: Corticotropin releasing factor, stress and behavior. Seminars in the Neurosciences 6:221–229, 1994

Koob GF, Sanna PP, Bloom FE: Neuroscience of addiction. Neuron 21:467–476, 1998 [PubMed]

Koob GF, Bartfai T, Roberts AJ: The use of molecular genetic approaches in the neuropharmacology of corticotropin-releasing factor. Int J Comp

Psychol 14:90–110, 2001

Lee JH, Lim Y, Wiederhold BK, et al: A functional magnetic resonance imaging (FMRI) study of cue-induced smoking craving in virtual environments.

Appl Psychophysiol Biofeedback 30:195–204, 2005 [PubMed]

Markou A, Koob GF: Post-cocaine anhedonia: an animal model of cocaine withdrawal. Neuropsychopharmacology 4:17–26, 1991 [PubMed]

Martin WR: Opioid antagonists. Pharmacol Rev 19:463–521, 1967 [PubMed]

McBride WJ, Murphy JM, Lumeng L, et al: Serotonin, dopamine and GABA involvement in alcohol drinking of selectively bred rats. Alcohol 7:199–205,

1990 [PubMed]

McFarland K, Kalivas PW: The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663, 2001

[PubMed]

Merlo-Pich E, Lorang M, Yeganeh M, et al: Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of

awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 15:5439–5447, 1995 [PubMed]

Morrisett RA: Potentiation of N-methyl-D-aspartate receptor-dependent afterdischarges in rat dentate gyrus following in vitro ethanol withdrawal.

Neurosci Lett 167:175–178, 1994 [PubMed]

Murphy JM, Stewart RB, Bell RL, et al: Phenotypic and genotypic characterization of the Indiana University rat lines selectively bred for high and low

alcohol preference. Behav Genet 32:363–388, 2002 [PubMed]

Nestler EJ: Historical review: molecular and cellular mechanisms of opiate and cocaine addiction. Trends Pharmacol Sci 25:210–218, 2004 [PubMed]

Olive MF, Koenig HN, Nannini MA, et al: Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and

reduction by subsequent ethanol intake. Pharmacol Biochem Behav 72:213–220, 2002 [PubMed]

Pandey SC: The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol

addiction. Pharmacol Ther 104:47–58, 2004 [PubMed]

Parsons LH, Justice JB Jr: Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis.

Brain Res 606:195–199, 1993 [PubMed]

Parsons LH, Weiss F, Koob GF: Serotonin-1B receptor stimulation enhances cocaine reinforcement. J Neurosci 18:10078–10089, 1998 [PubMed]

Paterson NE, Myers C, Markou A: Effects of repeated withdrawal from continuous amphetamine administration on brain reward function in rats.

Psychopharmacology (Berl) 152:440–446, 2000 [PubMed]

Rasmussen DD, Boldt BM, Bryant CA, et al: Chronic daily ethanol and withdrawal, 1: long-term changes in the hypothalamo-pituitary-adrenal axis.

Alcohol Clin Exp Res 24:1836–1849, 2000 [PubMed]

Risinger RC, Salmeron BJ, Ross TJ, et al: Neural correlates of high and craving during cocaine self-administration using BOLD fMRI. Neuroimage

26:1097–1108, 2005 [PubMed]

Rivier C, Bruhn T, Vale W: Effect of ethanol on the hypothalamic-pituitary-adrenal axis in the rat: role of corticotropin-releasing factor (CRF). J

Pharmacol Exp Ther 229:127–131, 1984 [PubMed]

Roberts AJ, Cole M, Koob GF: Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats. Alcohol Clin Exp Res

20:1289–1298, 1996 [PubMed]

Roy A, Pandey SC: The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after chronic

ethanol exposure. Alcohol Clin Exp Res 26:796–803, 2002 [PubMed]

Schulteis G, Markou A, Gold LH, et al: Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response

analysis. J Pharmacol Exp Ther 271:1391–1398, 1994 [PubMed]

Schulteis G, Markou A, Cole M, et al: Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci U S A 92:5880–5884, 1995

[PubMed]

Shaham Y, Shalev U, Lu L, et al: The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl)

168:3–20, 2003 [PubMed]

Shalev U, Grimm JW, Shaham Y: Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42, 2002 [PubMed]

Shippenberg TS, Koob GF: Recent advances in animal models of drug addiction and alcoholism, in Neuropsychopharmacology: The Fifth Generation

of Progress. Edited by Davis KL, Charney D, Coyle JT, et al. Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 1381–1397

Stinus L, Le Moal M, Koob GF: Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal.

Neuroscience 37:767–773, 1990 [PubMed]

Tiffany ST, Carter BL, Singleton EG: Challenges in the manipulation, assessment and interpretation of craving relevant variables. Addiction 95 (suppl

2):S177–S187, 2000

Tomkins DM, O’Neill MF: Effect of 5-HT(1B) receptor ligands on self-administration of ethanol in an operant procedure in rats. Pharmacol Biochem

Behav 66:129–136, 2000 [PubMed]

United Nations International Drug Control Programme and World Health Organization: Informal Expert Group Meeting on the Craving Mechanism,

Vienna, January 28–30, 1992 (report no. V92-54439T). Geneva, World Health Organization, 1992

Valdez GR, Roberts AJ, Chan K, et al: Increased ethanol self-administration and anxiety-like behavior during acute withdrawal and protracted

abstinence: regulation by corticotropin-releasing factor. Alcohol Clin Exp Res 26:1494–1501, 2002 [PubMed]

Volkow ND, Wang GJ, Telang F, et al: Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci

26:6583–6588, 2006 [PubMed]Print: Chapter 1. Neurobiology of Addiction http://www.psychiatryonline.com/popup.aspx?aID=344006&print=yes…

10 of 10

18/10/2008 10:03

Vorel SR, Liu X, Hayes RJ, et al: Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science 292:1175–1178, 2001 [PubMed]

Weiss F, Markou A, Lorang MT, et al: Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after

unlimited-access self-administration. Brain Res 593:314–318, 1992 [PubMed]

Weiss F, Parsons LH, Schulteis G, et al: Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and

5-hydroxytryptamine release in dependent rats. J Neurosci 16:3474–3485, 1996 [PubMed]

Weiss F, Ciccocioppo R, Parsons LH, et al: Compulsive drug-seeking behavior and relapse: neuroadaptation, stress, and conditioning factors, in The

Biological Basis of Cocaine Addiction (Annals of the New York Academy of Sciences Vol 937). Edited by Quinones-Jenab. New York, New York

Academy of Sciences, 2001, pp 1–26

Wong DF, Kuwabara H, Schretlen DJ, et al: Increased occupancy of dopamine receptors in human striatum during cue-elicited cocaine craving

[erratum in: Neuropsychopharmacology 2006; 32:256]. Neuropsychopharmacology 31:2716–2727, 2006 [PubMed]

SUGGESTED READING

Koob GF: Allostatic view of motivation: implications for psychopathology, in Motivational Factors in the Etiology of Drug Abuse (Nebraska Symposium on

Motivation, Vol 50). Edited by Bevins RA, Bardo MT. Lincoln, University of Nebraska Press, 2004, pp 1–18

Koob GF, Le Moal M: Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129, 2001

Koob GF, Le Moal M: Plasticity of reward neurocircuitry and the “dark side” of drug addiction. Nat Neurosci 8:1442–1444, 2005

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

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