Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acute reinforcing actions of drugs of abuse. Cocaine and amphetamines activate the release of dopamine in the nucleus accumbens and amygdala through direct actions on dopamine terminals. Opioids activate opioid receptors in the VTA, nucleus accumbens, and amygdala through direct or indirect actions via interneurons. Opioids facilitate the release of dopamine in the nucleus accumbens by an action either in the VTA or the nucleus accumbens, but also are hypothesized to activate elements independent of the dopamine system. Alcohol activates γ-aminobutyric acid-A (GABA_A) receptors or GABA release in the VTA, nucleus accumbens, and amygdala by either direct actions at the GABA_A receptor or through indirect release of GABA. Alcohol is hypothesized to facilitate the release of opioid peptides in the VTA, nucleus accumbens, and central nucleus of the amygdala. Alcohol facilitates the release of dopamine in the nucleus accumbens through an action either in the VTA or the nucleus accumbens. Nicotine activates nicotinic acetylcholine receptors in the VTA, nucleus accumbens, and amygdala, either directly or indirectly, through actions on interneurons. Cannabinoids activate cannabinoid CB₁ receptors in the VTA, nucleus accumbens, and amygdala. Cannabinoids facilitate the release of dopamine in the nucleus accumbens through an unknown mechanism either in the VTA or the nucleus accumbens. The blue arrows represent the interactions within the extended amygdala system hypothesized to have a key function in drug reinforcement. The medial forebrain bundle represents ascending and descending projections between the ventral forebrain (nucleus accumbens, olfactory tubercle, septal area) and the ventral midbrain (VTA) (not shown in figure for clarity). 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 (taken with permission from Koob, 2005).

Neural circuitry associated with the three stages of the addiction cycle. (a) Binge/intoxication stage. Reinforcing effects of drugs may engage reward neurotransmitters and associative mechanisms in the nucleus accumbens shell and core and then engage stimulus–response habits that depend on the dorsal striatum. Two major neurotransmitters mediating the rewarding effects of drugs of abuse are dopamine and opioid peptides. (b) Withdrawal/negative affect stage. The negative emotional state of withdrawal may engage the activation of the extended amygdala. The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the stria terminalis, central nucleus of the amygdala, and possibly a transition zone in the medial portion (or shell) of the nucleus accumbens. Major neurotransmitters in the extended amygdala hypothesized to have a function in negative reinforcement are corticotropin-releasing factor, norepinephrine, and dynorphin. Major projections of the extended amygdala are to the hypothalamus and brainstem. (c) Preoccupation/anticipation (craving) stage. This stage involves the processing of conditioned reinforcement in the BLA and the processing of contextual information by the hippocampus. Executive control depends on the prefrontal cortex and includes representation of contingencies, representation of outcomes, and their value and subjective states (ie, craving and, presumably, feelings) associated with drugs. The subjective effects termed drug craving in humans involve activation in functional imaging studies of the orbital and anterior cingulate cortices and temporal lobe, including the amygdala. A major neurotransmitter involved in the craving stage is glutamate localized in pathways from frontal regions and the BLA that project to the ventral striatum. Green/blue arrows, glutamatergic projections; orange arrows, dopaminergic projections; pink arrows, GABAergic projections; Acb, nucleus accumbens; BLA, basolateral amygdala; VTA, ventral tegmental area; SNc, substantia nigra pars compacta; VGP, ventral globus pallidus; DGP, dorsal globus pallidus; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; NE, norepinephrine; CRF, corticotropin-releasing factor; PIT, Pavlovian instrumental transfer (modified with permission from Koob et al, 2008a).

Brain images obtained at different times after administration for [¹¹C]-methamphetamine and for [¹¹C]cocaine (n=19 for each drug) showing axial planes at a level that transects the basal ganglia. Note the fast uptake of both drugs in the brain and the much slower clearance for [¹¹C]-methamphetamine than for [¹¹C]cocaine (taken with permission from Fowler et al, 2008).

Schematic drawing describing the sequential and cumulative effects of neuroadaptive changes hypothesized to contribute to the neuroplasticity that promotes compulsive drug-seeking. An early neuroadaptation, common to all drugs of abuse and observed after a single injection of cocaine, is increased excitability of the mesolimbic dopamine system reflected in long-term potentiation dependent on changes in glutamate activity. Subsequently, the activation of dopamine contributes to increased excitability of the ventral striatum with decreased glutamatergic activity during withdrawal and increased glutamatergic activity during drug-primed and cue-induced drug-seeking. The engagement of ventral striatal-pallidal-thalamic loops is hypothesized to translate to the dorsal striatum to contribute to engagement of habits and automaticity that resemble compulsive-like behavior. As compulsivity evolves into full-blown addiction, loss of function occurs in the frontal cortex systems that control executive function, contributing to poor decision-making and gain of function in the brain stress systems but contributing to incentive salience for drugs over natural reinforcers.

Neurocircuitry schematic illustrating the combination of neuroadaptations in the brain circuitry for the three stages of the addiction cycle that promote drug-seeking behavior in the addicted state. Note the activation of the ventral striatum/dorsal striatum/extended amygdala driven by cues through the hippocampus and basolateral amygdala and stress through the insula. The frontal cortex system is compromised, producing deficits in executive function and contributing to the incentive salience of drugs compared to natural reinforcers. Dopamine systems are compromised, and brain stress systems such as CRF are activated to reset further the salience of drugs and drug-related stimuli in the context of an aversive dysphoric state (modified with permission from Koob et al, 2008a).