Unpacking Ventral Pallidum GABA Neuron Contributions to Opioid Drug Reward in Rats.

Addiction is a heterogeneous disorder, and the specific psychological processes and neural mechanisms involved are hard to parse in humans. However, animal models allow the biological substrates of addiction-relevant behaviors to be examined one at a time. Ventral pallidum GABAergic neurons (VPGABA) are key players in circuits underlying natural and drug reward, but the exact behavioral processes to which they contribute are still not precisely defined. Here we systematically examined the necessity of VPGABA neurons for opioid and food reward seeking and taking behaviors, using reversible chemogenetic inhibition in GAD1:Cre rats. VPGABA inhibition revealed their preferential roles in highly-motivated pursuit and choice of heroin, but lesser involvement in unconditioned heroin effects, or in similarly motivated pursuit and choice of another rewarding opioid drug, remifentanil. Specifically, inhibiting VPGABA decreased cued- but not heroin-primed reinstatement of heroin seeking, decreased progressive ratio heroin pursuit, and increased selection of heroin over food when rats were forced to choose. In contrast, VPGABA inhibition did not alter remifentanil progressive ratio or choice of remifentanil over food, nor did it affect locomotion or food intake after heroin, or general arousal or anxiety-like states. These findings reveal a previously underappreciated specificity in the functions of VPGABA, and suggest that these cells play distinct roles in overtly similar behaviors rewarded by different classes of opioid drugs. Results also highlight the usefulness, when investigating the biological substrates of addiction, of parsing heterogeneities not just in neural circuits but also in the specific behavioral processes they mediate.