The Mesolimbic Dopamine System

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Research on the substrates of the addictive effects of drugs of abuse has underlined the role of dopamine cells, and in particular of the neurons originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc). This dopamine

Fig 4. Injection of corticosterone induces reinstatement of drug-seeking behavior. Administration of corticosterone induces an increase in the number of responses (nose pokes) in the device previously associated with cocaine (active hole), without modifying responding in the device without scheduled consequences (inactive hole). Peak effects are obtained for doses of corticosterone that are similar to those observed during stress; the descending limb of the curve is obtained for supra-physiological doses of corticosterone. (Modified from Deroche et al. [29]).

Fig 4. Injection of corticosterone induces reinstatement of drug-seeking behavior. Administration of corticosterone induces an increase in the number of responses (nose pokes) in the device previously associated with cocaine (active hole), without modifying responding in the device without scheduled consequences (inactive hole). Peak effects are obtained for doses of corticosterone that are similar to those observed during stress; the descending limb of the curve is obtained for supra-physiological doses of corticosterone. (Modified from Deroche et al. [29]).

pathway plays an important role in natural reward-related behaviors, such as seeking for food, sexual partners, or novel stimuli (84,85). Numerous studies have shown that different addictive drugs, such as psychostimulants, opioids, nicotine, and alcohol, all share the common property of increasing NAc dopamine (86-89). In addition, lesions of the NAc, or of neurons projecting to the NAc, decrease self-administration of these drugs (38,39,90,91), and dopamine receptor agonists or antagonists, can respectively increase or decrease the rewarding properties of psychostimulants (92-99). The role of the meso-accumbens dopamine projection in drug addiction is further underlined by findings showing that the activity of dopamine neurons codes for the rewarding aspects of environmental stimuli (100) and that increased activity of these cells is associated with enhanced vulnerability to drug addiction (101). In addition, animals with increased vulnerability to drugs also display increased dopamine levels in the NAc in basal conditions, in response to psychostimulant drugs and to stress (102-105).

Dopaminergic hyperactivity also seems to play an important role in stress-mediated increase in vulnerability to drugs. Following the work by Thierry and collaborators (106), numerous studies have analyzed the relationship between stress and dopaminergic activity (for review, see ref. 107). It has been hypothesized that dopaminergic hyperactivity could be a mechanism by which stress increases drug responding. Thus, stress-induced increase in drug effects is associated with increased dopamine cell activity (65,108) as well as with increased levels of dopamine in the NAc in basal conditions, following administration of psychostimulants, or a subsequent stressor (62,71,109-116).

In the past decade, studies on drug addiction have given a particularly important role to the "shell" of the NAc, a functionally and anatomically distinct subset of this nucleus (for review, see ref. 117). Thus, addictive drugs preferentially increase dopamine trans mission in the shell of the NAc (102,118-121), and dopamine or dopamine receptor antagonists administered in the shell can modify drug self-administration behavior (122). In addition, animals will self-administer drugs with addictive potential preferentially in the shell of the NAc (123,124). It should be noted that although the shell seems to play a key role in brain reward mechanisms, the "core" of the NAc also has an important role; this substructure seems particularly involved in the processing of reward-related cues (for review, see ref. 125).

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