SAR-39684-the-neurocircuitry-of-illicit-psychostimulant-addiction--an-_020713.pdf

43 of these regions the nac described above and the

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motor control but also in PFC function. 43 Of these regions, the NAc (described above) and the DS (described below) are most frequently examined with respect to addiction. Thus, only a brief description of the modulatory role of the basal ganglia in addiction-relevant circuits will be mentioned here. The overall output of the basal ganglia is predominantly via the thalamus, which then projects back to the PFC to form cortico-striatal-thalamo-cortical (CSTC) loops. Three CSTC loops are proposed to modulate executive function, action selection, and behavioral inhibition. In the dorsolateral prefrontal circuit, the basal ganglia primarily modulate the identification and selection of goals, including rewards. 44 The OFC circuit modulates decision-making and impulsivity, and the anterior cingulate circuit modulates the assessment of consequences. 44 These circuits are modulated by dopaminergic inputs from the VTA to ultimately guide behaviors relevant to addiction, including the persistence and narrowing of the behavioral repertoire toward drug seeking, and continued drug use despite negative consequences. 43–45 The DS (also referred to as the caudate-putamen in primates) is associated with transitions from goal-directed to habitual drug use, due in part to its role in stimulus–response learning. 28,46 As described above, the initial rewarding and reinforcing effects of drugs of abuse are mediated by increases in extracellular DA in the NAc shell, and after continued drug use in the NAc core. 47,48 After prolonged drug use, drug-associated cues produce increases in extracellular DA levels in the DS and not in the NAc. 49 This lends to the notion that a shift in the relative engagement from the ventral to the dorsal striatum underlies the progression from initial, voluntary drug use to habitual and compulsive drug use. 28 In addition to DA, recent evidence indicates that glutamatergic transmission in the DS is important for drug-induced adaptations and plasticity within the DS. 50 Learning and memory systems Hippocampus The HPC is highly involved in normal spatial memory function, in part due to its critical involvement in the integration of contextual and environmental cues or information. 51 Interestingly, the ventral subiculum, the primary output of the HPC, projects to several limbic regions, including the NAc and DS. 52 The ventral subiculum has been found to play a key role in cocaine-seeking behavior, suggesting the importance of contextual information in psychostimulant addiction. 53 In addition, the ventral subiculum-to-NAc pathway has been implicated in psychostimulant sensitization in a DA-dependent manner. 54,55 Recently, it was found that a trans-synaptic link between the CA3 region of the HPC and the VTA may also mediate the ability of contextual information to modulate motivational behaviors.
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