Friday, March 14, 2025
3/14/2025
Project Summary Addiction, and opioid use disorder (OUD) in particular, is a scourge on American life. Though we know much from animal models about how opioid drugs act on the brain, we have yet to develop new OUD treatments based on this knowledge. Why is this? Our lab, like others in recent years, have argued that in part it is due to a lack of translationally-relevant rodent models that capture the key behavioral features of addiction, such as the maladaptive, compulsive, and relapsing use that develops in a subset of individuals. In humans, OUD is characterized by continued use of opioids despite negative consequences, preoccupation with using these drugs, and relapse to drug use after quitting, and for long-lasting opioids like heroin, also escalation of use, tolerance, and withdrawal. Each of these translationally-relevant behavioral phenomena can now be modelled in rodents, but the neural networks underlying each of them are yet poorly understood. The ventral pallidum (VP), and especially its dense projections to the ventral tegmental area (VTA), have drawn increasing attention for their potent roles in motivation and addiction. We recently showed VP neurons are essential for translationally-relevant cocaine relapse-like behavior, and that GABAergic VP neurons (VPGABA) and their projections to VTA are specifically responsible for a range of strongly motivated behaviors—presumably via interactions with wider neural networks of motivation. We hope that by understanding how these neural networks function during behaviors that capture key aspects of OUD, we can leverage this information to develop new neuroscience-based treatment strategies. Here, we systematically dissect the involvement of VPGABA neurons, and the wider reward and aversion networks they modulate, in OUD-relevant behaviors. In well-validated GAD1:Cre transgenic rats, we use Cre and Flp-dependent chemogenetic manipulations to show how VPGABA neurons 1) modulate wider networks underlying opioid relapse, 2) participate via their functionally-segregated outputs in appetitive aspects of OUD, and 3) how these pathways mediate aversive aspects of OUD. We hypothesize that VPGABA neurons modulate wider neural networks to generate OUD behaviors, and that inhibiting this key pathway will reduce compulsive drug seeking.
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