Unraveling the molecular mechanisms of choosing cocaine over healthy rewards

Animal research on addiction has a translational problem.

Despite decades of research, advances in basic neuroscience have had limited impact on the treatment of addictive disorders, suggesting that the widely used models do not account for the complexity of cocaine use disorder (CUD).

This impasse is at least partly due to limitations in the construct validity of animal models of addiction, which rarely incorporate a critical feature of human addiction: individual vulnerability to choice of drug over high value alternative non-drug rewards.

To address this gap, I established an operant rat model of choice between drugs and healthy rewards and identified that decreased expression of the GABA transporter GAT-3 within central amygdala (CeA) was causal for alcohol choice behavior and translated to humans. Our preliminary data suggest that this mechanism is also critical for cocaine-related behaviors.

Using our translationally relevant choice-based animal models combined with state-of-the-art viral vector, fiber photometry and RNA sequencing approaches, we will investigate the role of GAT-3 in CeA and Nucleus Accumbens in CUD-like behaviors.

We will also complement this approach with an unbiased discovery effort to identify other mechanisms mediating choice of cocaine over healthy rewards. Finally, we will evaluate a novel target for CUD: positive allosteric modulators of GABAB receptors. This proposal will help identify molecular targets for much needed CUD pharmacotherapies.