Alcohol use disorder (AUD) is a debilitating and life-long addictive disease with significant public health costs. Individuals suffering from AUD exhibit compulsive alcohol drinking, defined as drinking that is resistant to negative or aversive consequences. While there is a growing recognition in the field of the need for more relevant models of addictive behavior, there is still relatively little known about the neural circuits engaged during compulsive drug seeking. Studies in humans and rats suggest a role for the nucleus accumbens (NAc) core in compulsive-like alcohol drinking. D1-neurons are a subpopulation of neurons in the NAc that project to the midbrain and the ventral pallidum (VP). Activity in D1-neurons is critical in controlling motivated and drug- seeking behaviors. Convergent findings from preclinical models of alcohol dependence and obsessive- compulsive disorder suggest the metabotropic glutamate receptor 5 (mGluR5) may play a role in biasing striatal output toward D1-neurons. Given that alcohol exposure increases mGluR5 expression in the NAc, mGluR5 expression on D1-neurons of the NAc core may serve as a key molecular contributor to compulsive- like alcohol drinking. Our experiments will test this hypothesis through completion of two primary specific aims: We will determine whether 1) mGluR5 expression on NAc core D1-neurons and 2) activity in D1-neuron projections to the VP promote aversion-resistant alcohol drinking in mice. Aversion-resistant drinking will be tested using a drinking in the dark model in which the bitter tastant quinine is added to ethanol. Collectively, completion of these aims will characterize the contribution of mGluR5 on NAc core D1-neuron projections to compulsive alcohol drinking, thereby delineating one of the mechanisms by which alcohol exposure can lead to addictive behavior. Furthermore, we will train undergraduate students in a broad array of modern techniques in behavioral neuroscience, such as chemogenetics, site-specific pharmacology, quantitative real-time PCR, and flow cytometry. These activities will strengthen opportunities for behavioral neuroscience research at Miami University and build institutional knowledge in the use of flow cytometry for neuroscience research.
Compulsive alcohol drinking is responsible for many of the symptoms of alcohol use disorder, which currently afflicts approximately 7% of adults in the United States. This project will use a mouse model of aversion- resistant alcohol drinking to investigate how neurons in the nucleus accumbens promote drinking despite negative consequences. Understanding the neural mechanisms responsible for alcohol use disorder will inform future therapies and treatments for the disease.
