Modeling cocaine relapse in rodents: Behavioral considerations and circuit mechanisms

Abstract

Addiction is a chronic relapsing disorder, in that most addicted individuals who choose to quit taking drugs fail to maintain abstinence in the long-term. Relapse is especially likely when recovering addicts encounter risk factors like small "priming" doses of drug, stress, or drug-associated cues and locations. In rodents, these same factors reinstate cocaine seeking after a period of abstinence, and extensive preclinical work has used priming, stress, or cue reinstatement models to uncover brain circuits underlying cocaine reinstatement. Here, we review common rat models of cocaine relapse, and discuss how specific features of each model influence the neural circuits recruited during reinstated drug seeking. To illustrate this point, we highlight the surprisingly specific roles played by ventral pallidum subcircuits in cocaine seeking reinstated by either cocaine-associated cues, or cocaine itself. One goal of such studies is to identify, and eventually to reverse the specific circuit activity that underlies the inability of some humans to control their drug use. Based on preclinical findings, we posit that circuit activity in humans also differs based on the triggers that precipitate craving and relapse, and that associated neural responses could help predict the triggers most likely to elicit relapse in a given person. If so, examining circuit activity could facilitate diagnosis of subgroups of addicted people, allowing individualized treatment based on the most problematic risk factors.

Persistent effects of obesity: a neuroplasticity hypothesis

“…This may be relevant to the development of substance use disorder, given the strong associations between stress and drug use in both humans and animals. [42][43][44] Accumbal MSNs in mice susceptible to stress-induced depressive-like phenotypes incorporated more synaptic calciumpermeable, glutamate ionotropic receptor AMPA type subunit 2 (GluA2)-lacking AMPARs relative to MSNs from control or resilient mice. 45,46 This suggests that related plasticity mechanisms in mesolimbic circuitry may underlie stress susceptibility and drug abuse.…”

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

“…For this reason, manipulations that strengthen extinction memories have been proposed as useful strategies that help to maintain abstinence (Everitt, 2014;Farrell et al, 2018;Kalivas and Volkow, 2011). Our results show a lack of effect of CBD (20 mg/kg) on cocaine seeking behaviors during extinction conditions.…”

Granulocyte-Colony Stimulating Factor reduces cocaine-seeking and downregulates glutamatergic synaptic proteins in medial prefrontal cortex

“…Two of the most common ways to assess relapse in preclinical models are reinstatement after extinction and re-exposure to drug cues after a period of abstinence (Grimm et al, 2001;Dong et al, 2017;Farrell et al, 2018). All models of relapse involve recall of previously learned response-outcome contingencies and require intact functioning of the mesolimbic dopaminergic system (Kalivas et al, 2005;Hyman et al, 2006;Farrell et al, 2018), parts of which are known to be affected by G-CSF Brady et al, 2019).…”

“…Two of the most common ways to assess relapse in preclinical models are reinstatement after extinction and re-exposure to drug cues after a period of abstinence (Grimm et al, 2001;Dong et al, 2017;Farrell et al, 2018). All models of relapse involve recall of previously learned response-outcome contingencies and require intact functioning of the mesolimbic dopaminergic system (Kalivas et al, 2005;Hyman et al, 2006;Farrell et al, 2018), parts of which are known to be affected by G-CSF Brady et al, 2019). Active self-administration, extinction, and reinstatement all recruit NAc and medial prefrontal cortex (mPFC) but extinction and reinstatement more heavily rely upon mPFC (Kalivas and McFarland, 2003;Hyman et al, 2006;Peters et al, 2009), making these areas attractive targets of G-CSF action in cocaine reinforcement, extinction, and reinstatement.…”