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

Abstract

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.

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

“…We have previously shown a significant persistent decrease in the dopaminergic population activity recorded in the VTA after 7 and 30 days of abstinence from extended cocaine intake (25 days) (Salin et al, 2021). Here, we investigated potential changes in DA VTA activity after a shorter 10-day period of cocaine selfadministration, in the early phase of abstinence (withdrawal days 1-3) and after protracted abstinence (withdrawal days 26-45).…”

“…The sample size and animal numbers were determined by power analysis of pre-existing data (Belujon and Grace, 2014;Chang and Grace, 2014;Belujon et al, 2016;Salin et al, 2021).…”

“…For DA neurons, recording electrode was lowered using a microdrive through the right VTA in 9 sequential vertical tracks separated by 0.2mm (Supplementary figure 1). Spontaneously active cells encountered identified as DA neurons (online analysis) were recorded to determine population activity as previously described (Salin et al, 2021). Single-unit activity recorded from the VTA was amplified 10 times, filtered (low pass: 30 Hz; high pass: 16 kHz), and further amplified 50 times (Multiclamp 700b, Axon Instruments, Union City, CA).…”

“…Chronic cocaine produces persistent neuroadaptations in brain networks that underlie long-term risks of relapse and incubation of drug craving (van Huijstee and Mansvelder, 2015). Rewarding properties of psychostimulants such as cocaine are associated with hyperdopaminergic state (Wise and Hoffman, 1992) whereas acute withdrawal from acute and chronic psychostimulants leads to a hypodopaminergic state, specifically in the mesolimbic system (Shen et al, 2007;Belujon et al, 2016;Salin et al, 2021), leading to hedonic deficits (Wise, 2008;Belujon and Grace, 2017). Reduction of DA activity is also observed after long abstinence (Diana et al, 1996;Salin et al, 2021); this reduction could be involved in dysphoria described after protracted abstinence (Haake et al, 2019).…”

Integrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease

“…Animals were able to learn to selfadminister drugs into the VTA (nicotine: [137,138], opiates: [139][140][141][142], cocaine: [143][144][145], ethanol: [146,147]), and this effect was diminished with the addition of dopamine antagonists or with lesions to the VTA DA neurons [137,138,148,149]. Moreover, this seems to be specific to the VTA and the regions it projects, as the SNpc has almost no release of dopamine in response to intravenous drug administration or abstinence [150,151]. This is thus broadly consistent with the hypothesis that circuit-specific DA neuromodulation underlies addiction symptomatology.…”