The amygdala-ventral pallidum pathway contributes to a hypodopaminergic state in the ventral tegmental area during protracted abstinence from chronic cocaine.

BACKGROUND AND PURPOSE: Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug-seeking behaviour. Decreases of dopamine (DA) release and DA neuronal activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence, but the mechanisms underlying these neuroadaptations are not well understood. We investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala [BLA]-ventral pallidum [VP] pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine. EXPERIMENTAL APPROACH: In a model of cocaine self-administration, we performed in vivo electrophysiological recordings of DA VTA neurons and BLA neurons from anaesthetised rats during early and protracted abstinence and evaluated the involvement of the BLA-VP pathway using a pharmacological approach. KEY RESULTS: We found significant decreases in VTA DA population activity and significant increases in BLA activity after protracted but not after short-term abstinence from chronic cocaine. The decrease in VTA DA activity was restored by pharmacological inhibition of the activity of either the BLA or the VP, suggesting that these regions exert a negative influence on DA activity. CONCLUSION AND IMPLICATIONS: Our study sheds new lights on neuroadaptations occurring during incubation of craving leading to relapse. In particular, we describe the involvement of the BLA-VP pathway in cocaine-induced decreases of DA activity in the VTA. This study adds important information about the specific brain network dysfunctions underlying hypodopaminergic activity during abstinence.

Protracted Abstinence From Extended Cocaine Self-Administration Is Associated With Hypodopaminergic Activity in the VTA but Not in the SNc.

The chronic relapsing nature of cocaine addiction suggests that chronic cocaine exposure produces persistent neuroadaptations that may be temporally and regionally dynamic in brain areas such as the dopaminergic (DA) system. We have previously shown altered metabolism of DA-target structures, the ventral and dorsal striatum, between early and late abstinence. However, specific changes within the midbrain DA system were not investigated. Here, we investigated potential time- and region-specific changes of activity in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) in rats that had extended or limited access to cocaine and later underwent a period of abstinence. We found that DA activity is decreased only in the VTA in rats with extended access to cocaine, with no changes in SNc DA activity. These changes in VTA DA activity may participate in the negative emotional state and the incubation of drug seeking that occur during abstinence from cocaine.