Addiction: beyond dopamine reward circuitry

Abstract

Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Pharmacokinetics of stimulant drugs in the human brain and relationship to the “high.” (A) Axial brain images of the distribution of [11C]cocaine, [11C]MP, and [11C]methamphetamine at different times (minutes) after its administration. (B) Time activity curve for the concentration of [11C]cocaine, [11C]MP, and [11C]methamphetamine in striatum alongside the temporal course for the high experienced after i.v. administration of these drugs. Note that the fast brain uptake for these drugs corresponds to the temporal course of the high, which suggests that the high is associated with the “rate of DA increases.” In contrast, their clearance shows a correspondence with the high for cocaine and for methamphetamine but not for MP. The difference between MP and cocaine may reflect the differences in their rate of clearance and that between MP and methamphetamine may reflect their different mechanisms of action. Specifically, because MP and cocaine increase DA by blocking DA transporters, the DA increases are terminated by autoreceptor activation, which inhibits DA release. For cocaine, its fast rate of clearance (20-min half-life in brain) results in short-lasting autoreceptor activation, whereas for MP, its slower clearance (60-min half-life) results in long-lasting inhibition of DA release by autoreceptors, which terminates the high even though the drug is still in the brain. In contrast, methamphetamine, which is a DA releaser, is not sensitive to autoreceptor activation; thus, DA increases are not terminated by this mechanism, accounting for the longer lasting duration of the high. Modified from ref. . Copyright (1995) American Medical Association. All rights reserved. Reprinted from ref. . Copyright (2008), with permission from Elsevier.

Fig. 2.

DA changes induced by i.v. MP in controls and in active cocaine-addicted subjects. (A) Average nondisplaceable biding potential (BPND) images of [11C]raclopride in active cocaine-addicted subjects (n = 19) and in controls (n = 24) tested after placebo and after i.v. MP. (B) D2R availability (BPND) in caudate, putamen, and ventral striatum after placebo (blue) and after MP (red) in controls and in cocaine-addicted subjects. MP reduced D2R in controls but not in cocaine-addicted subjects. Note that cocaine abusers show both decreases in baseline striatal D2R availability (placebo measure) and decreases in DA release when given i.v. MP (measured as decreases in D2R availability from baseline). Although one could question the extent to which the low striatal D2R availability in cocaine-addicted subject limits the ability to detect further decreases from MP, the fact that cocaine-addicted subjects show reductions in D2R availability when exposed to cocaine cues (Fig. 3) indicates that the attenuated effects of MP on [11C]raclopride binding reflect decreased DA release.

Fig. 3.

DA changes induced by conditioned cues in active cocaine-addicted subjects. (A) Average nondisplaceable biding potential (BPND) images of [11C]raclopride in cocaine-addicted subjects (n = 17) tested while viewing a neutral video (nature scenes) and while viewing a cocaine-cues video (subjects administering cocaine). (B) D2R availability (BPND) in caudate, putamen, and ventral striatum for the neutral video (blue) and the cocaine-cues video (red). The cocaine cues decreased D2R in caudate and putamen. (C) Correlations between changes in D2R (reflecting DA increases) and self-reports of cocaine craving induced by the cocaine-cues video. Modified from ref. .

Fig. 4.

Correlations between striatal D2R availability and metabolism in prefrontal brain regions. (A) Axial brain images for a control and for a cocaine-addicted subject for baseline images of D2R availability in striatum (obtained with [11C]raclopride) and of brain glucose metabolism in OFC (obtained with [18F]FDG). (B) Correlations between striatal D2R and metabolism in OFC in cocaine-addicted and methamphetamine-addicted subjects. Reprinted from ref. , Copyright (2009), with permission from Elsevier.

Fig. 5.

Model proposing a network of interacting circuits underlying addiction: reward (nucleus accumbens, VTA, and ventral pallidum), conditioning/memory (amygdala, medial OFC for attribution of saliency, hippocampus, and dorsal striatum for habits), executive control (DLPFC, ACC, inferior frontal cortex, and lateral OFC), and motivation/drive (medial OFC for attribution of saliency, ventral ACC, VTA, SN, dorsal striatum, and motor cortex). Nac, nucleus accumbens. (A) When these circuits are balanced, this results in proper inhibitory control and decision making. (B) During addiction, when the enhanced expectation value of the drug in the reward, motivation, and memory circuits overcomes the control circuit, this favors a positive-feedback loop initiated by the consumption of the drug and perpetuated by the enhanced activation of the motivation/drive and memory circuits. These circuits also interact with circuits involved in mood regulation, including stress reactivity (which involves the amygdala and hypothalamus) and interoception (which involves the insula and ACC and contributes to awareness of craving). Several neurotransmitters are implicated in these neuroadaptations, including glutamate, GABA, norepinephrine, corticotropic-releasing factor, and opioid receptors. CRF, corticotropic-releasing factor; NE, norepinephrine. Modified with permission from ref. ; permission conveyed through Copyright Clearance Center, Inc.