Extinction vs. Abstinence: A Review of the Molecular and Circuit Consequences of Different Post-Cocaine Experiences

Abstract

The intravenous cocaine self-administration model is widely used to characterize the neurobiology of cocaine seeking. When studies are aimed at understanding relapse to cocaine-seeking, a post-cocaine abstinence period is imposed, followed by “relapse” tests to assess the ability of drug-related stimuli (“primes”) to evoke the resumption of the instrumental response previously made to obtain cocaine. Here, we review the literature on the impact of post-cocaine abstinence procedures on neurobiology, finding that the prelimbic and infralimbic regions of the prefrontal cortex are recruited by extinction training, and are not part of the relapse circuitry when extinction training does not occur. Pairing cocaine infusions with discrete cues recruits the involvement of the NA, which together with the dorsal striatum, is a key part of the relapse circuit regardless of abstinence procedures. Differences in molecular adaptations in the NA core include increased expression of GluN1 and glutamate receptor signaling partners after extinction training. AMPA receptors and glutamate transporters are similarly affected by abstinence and extinction. Glutamate receptor antagonists show efficacy at reducing relapse following extinction and abstinence, with a modest increase in efficacy of compounds that restore glutamate homeostasis after extinction training. Imaging studies in humans reveal cocaine-induced adaptations that are similar to those produced after extinction training. Thus, while instrumental extinction training does not have face validity, its use does not produce adaptations distinct from human cocaine users.

Profiling prefrontal cortex protein expression in rats exhibiting an incubation of cocaine craving following short-access self-administration procedures

“…This is our first examination for incubation-related changes in iGlu receptor expression within PFC subregions and as such, we employed conventional immunoblotting procedures on whole-cell lysates that cannot inform as to the membrane localization of our receptor subunits or the functional status of the receptors. Thus, our failure to detect incubation-associated changes in iGlu receptor subunit expression within PFC may reflect a lack of subcellular specificity in our results or regional distinctions in the glutamate-related effects of cocaine withdrawal as reported in the literature [e.g., (48,(64)(65)(66); see review (67)]. Alternatively, a recent study implicated time-dependent changes in the plasma membrane expression of the magnesium-insensitive and calcium-impermeable GluN3 subunit of the NMDA receptor within the NAC core as important for incubated cocaine craving (44).…”

Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens

“…Withdrawal and extinction phases have been classically modeled and studied in animals for decades 18,[65][66][67][68] . These strategies have been largely centered on applying forced abstinence either in home-cages or under full extinction conditions.…”

Enhanced expression of parvalbumin and perineuronal nets in the medial prefrontal cortex after extended‐access cocaine self‐administration in rats

“…Enzymatic PNN degradation decreases the excitability of PV neurons, 11 and one might therefore expect a disinhibition of pyramidal neurons via decreased GABAergic transmission onto pyramidal neurons that in turn might be expected to increase, rather than decrease, reinstatement behaviour. 3,[29][30][31] Although speculative, the mechanism by which PNN removal diminished cue-induced reinstatement may instead rest on an inability of PV neurons to synchronize pyramidal neuron output necessary to form discrete activated ensembles expressed during memory. A reduced ability to fire at high rates would disrupt their precise firing patterns.…”

“…28 The mPFC is a key contributor to reinstatement after both abstinence and extinction. 3,[29][30][31] Despite these studies, none have compared abstinence versus extinction sessions after extended cocaine access to determine the extent to which these manipulations alter the intensity of PNNs or their underlying PV interneurons in the mPFC, nor have they examined subsequent cue-induced reinstatement. Further, no studies have tested whether PNN removal after extended access prevents the incubation of cocaine seeking during cue-induced reinstatement.…”