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. Animal models are useful in this regard, as biological substrates of addiction-relevant behaviors can be examined one at a time. Ventral pallidum GABAergic neurons (VP^GABA), 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 VP^GABA neurons for opioid and food reward seeking and taking behaviors, using reversible chemogenetic inhibition in GAD1:Cre, predominately female, rats. We found that VP^GABA 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 VP^GABA 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, VP^GABA 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 VP^GABA neurons, and show they may 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.Significance Statement Opioid addiction is a heterogeneous disorder, which makes it difficult to pinpoint the neural processes underlying its various components. Here we show that VP^GABA neurons play surprisingly specific roles in behaviors relevant to opioid use disorder. VP^GABA inhibition selectively reduced choice of heroin over food, highly-motivated heroin progressive ratio self-administration, and cue-triggered reinstatement, yet spared other heroin-induced behaviors. In contrast, closely matched behaviors motivated by the similarly-reinforcing fentanyl derivative remifentanil including choice of remifentanil over food, were spared. These results reveal unexpected reward- and process-specific functions of VP^GABA neurons, highlighting the importance of comprehensive behavioral profiling in such experiments for identifying how neural mechanisms depend upon particular drugs and behavioral models-an essential step toward developing effective addiction interventions.