Ventral pallidum GABA neurons bidirectionally control opioid relapse across rat behavioral models

Opioid addiction is a chronic, relapsing disorder. Whether addicted individuals are forced to abstain or they decide themselves to quit using drugs, relapse rates are high-especially upon encountering contexts and stimuli associated with prior opioid use. Rodents similarly show context- and cue-induced reinstatement of drug seeking following abstinence, and intriguingly, the neural circuits underlying these relapse-like behaviors differ when abstinence is involuntarily imposed, responding is extinguished, or animals decide themselves to cease taking drug. Here, we employ two complementary rat behavioral models of relapse-like behavior for the highly reinforcing opioid drug remifentanil, and asked whether GABAergic neurons in the ventral pallidum (VP^GABA) control opioid seeking under these behavioral conditions. Specifically, we asked how chemogenetically stimulating VP^GABA neurons with clozapine-N-oxide (CNO) influences the ability of contextual or discrete remifentanil-paired cues to reinstate drug seeking following either voluntary abstinence (punishment-induced; Group^Punish), or extinction training (Group^Ext). In Group^Punish rats, we also chemogenetically inhibited VP^GABA neurons, and examined spontaneous VP activity (Fos) during cued reinstatement. In both Group^Punish and Group^Ext rats, stimulating Gq-signaling in VP^GABA neurons augmented remifentanil reinstatement in a cue- and context-dependent manner. Conversely, engaging inhibitory Gi-signaling in VP^GABA neurons in Group^Punish suppressed cue-induced reinstatement, and cue-triggered seeking was correlated with Fos expression in rostral, but not caudal VP. Neither stimulating nor inhibiting VP^GABA neurons influenced unpunished remifentanil self-administration. We conclude that VP^GABA neurons bidirectionally control opioid seeking regardless of the specific relapse model employed, highlighting their fundamental role in opioid relapse-like behavior across behavioral models, and potentially across species.