Brandon M. Fritz, M.S. - US grants

The marked lack of treatment options for individuals suffering from alcohol use disorders (AUDs) raises a critical need for alternative approaches to study how alcohol exposure persistently alters neurocircuitry. Adenosine A1 receptors (A1Rs) are intriguing targets for alcohol-induced synaptic and behavioral plasticity. Alterations in these processes are related to key phenotypes observed in AUDs, such as functional tolerance (i.e. reduced motor intoxication as a consequence of repeated exposure) which contributes to alcohol-related harms (e.g. driving under the influence). A1Rs influence alcohol consumption, intoxication, and functional tolerance in preclinical models, although the mechanisms and neurocircuitry involved are poorly understood. Thus, there is a knowledge gap regarding A1Rs as significant mediators of plasticity driven by repeated alcohol exposure. The dorsal striatum (DS), a brain region involved in various aspects of behavioral flexibility with regard to alcohol (e.g. functional tolerance) is a likely target for alcohol effects on A1R neurobehavioral plasticity. Approximately 95% of cells in the striatum are GABAergic medium spiny neurons (MSNs) which indirectly (via basal ganglia structures and thalamic loops) regulate output to a variety of motor cortical areas. The DS is comprised of functionally heterogeneous medial (DMS) and lateral (DLS) subregions, each receiving distinct excitatory glutamatergic inputs driving MSN activity, including projections from sensorimotor and prefrontal cortices as well as a variety of thalamic nuclei. Prior work has shown that alcohol exposure disrupts synaptic long-term depression (LTD) plasticity mediated by other systems (e.g. endocannabinoids) in the DLS. However, electrophysiology studies have not consistently differentiated between the DMS and DLS and alcohol effects on A1R plasticity are unknown. In addition, the role of DS A1Rs in the adaptive process of functional tolerance has yet to be explored. The central hypothesis is that A1Rs within the DS are mediators of alcohol-induced alterations in glutamate plasticity and behavioral tolerance and that the functional dissociation of the DMS/DLS is a critical factor in these effects. Knowledge of the involvement of these A1Rs in critical neurobehavioral adaptations will move us closer to the long-term goal of understanding how alcohol produces persistent changes in the central adenosine system that influence behavior. Towards this goal, slice electrophysiology, optogenetics, and transgenic mouse approaches will be combined to address the synapse-specificity (corticostriatal vs. thalamostriatal) of alcohol exposure effects on A1R-LTD at MSN synapses in the functionally heterogeneous subregions of the DS (DMS & DLS). In addition, alcohol functional tolerance will be examined following DMS and DLS viral-mediated deletion of A1Rs. With these data, we will better understand how alcohol exposure produces lasting effects on excitatory neurotransmission in the DS as well as the mechanisms, neurocircuitry, and time course of alcohol functional tolerance development.