PROJECT ABSTRACT 40% of patients who are diagnosed with cocaine use disorder are considered to have a severe cocaine use disorder meeting six or more criteria from the DSM-5. The lack of effective medication for cocaine use disorder demonstrates an urgent need to better understand the effect of cocaine on neurobiology and behaviors. Cocaine- induced increase in striatal dopamine release is essential for cocaine reinforcement, however, the mechanisms of striatal circuit adaptations inducing cocaine seeking is not well established. The overall objective of this proposal is to determine the mechanism by which cocaine affects striatopallidal circuit activity to facilitate cocaine seeking and taking. My central hypothesis is that 1) cocaine-induced increases of the opioid peptide, enkephalin in the striatum suppresses GABA transmission from striatal neurons via δ/µ opioid receptors and, as a result, disinhibits VP GABA neurons, and 2) striatal enkephalin plays a key role in cocaine seeking. Aim 1: Determine the necessity of striatal enkephalin in cocaine-induced adaptations in the striatopallidal circuit: Based on our preliminary data and previous findings, I hypothesize that increase in enkephalin in the striatum during withdrawal from a history of cocaine exposure leads to suppression of GABA transmission from enkephalin-expressing striatal neurons, which increases excitability of the postsynaptic VP GABA neurons. We will test this by performing whole-cell electrophysiology recordings in D2-MSN-selective enkephalin knockouts with a history of cocaine exposure, and measure GABA transmission from striatal neurons onto VP GABA neurons and VP neuron excitability. The use of exogenous enkephalin and opioid receptor selective antagonists will confirm striatal enkephalin and determine the type of opioid receptor as a mechanism for depression of GABA transmission and increased excitability. Immunohistochemistry will confirm the type of recorded VP neurons. Aim 2: Determine the role of striatal enkephalin in cocaine self-administration: Based on our preliminary data, I hypothesize that striatal enkephalin facilitates self-administration and cocaine seeking. We will test this by performing operant self-administration using striatal neuron-selective enkephalin knockouts and examine the effect of striatal enkephalin deletion on cocaine seeking and taking and the motivation for cocaine. Through completion of this proposal, and under the guidance of my sponsors, Drs. Lauren Dobbs and Robert Messing, who are experts in substance use disorder research, I will receive extensive training to develop professional skills, expand my laboratory skillset, and improve my communication skills for post-doctorate research career in neuroscience. Combined with the training resources and expansive research expertise available at University of Texas at Austin, I will be well-supported throughout this fellowship and make a successful transition to a post-doctoral research position...