PROJECT SUMMARY Cocaine use disorder represents a major public health challenge, and novel treatment approaches are urgently needed. Tobacco usage is highly co-morbid with cocaine use disorder, and at present, it is not known whether/how nicotinic signal transduction modulates the brain's response to cocaine. We hypothesize that tobacco usage contributes to cocaine use, and we will model this research question using a rat model system. We will probe the mechanistic underpinnings of nicotinic modulation of cocaine reinforcement, focusing on identifying key nicotine receptors and nerve cell types in the brain's reward circuit. In the R21 phase, we will validate a set of molecular tools that we developed in a previously funded project. These tools allow us to reduce or eliminate the expression of specific nicotine receptors in precise cell types in the brain. We'll verify that these tools work for their purpose in this project, examining how well they reduce nicotine receptor function in cellular assays (Aim 1). This involves single-cell patch-clamp recordings and fiber photometry. In R21 Aim 2, we will determine whether/how nicotine receptor functional attenuation impacts cocaine self-administration behavior. Specific manipulations that impact cocaine reinforcement will be confirmed with replication studies and other control experiments then advanced to the R33 phase for further investigation. In the R33, we will further probe the mechanisms by which nicotine receptors modulate cocaine reinforcement. R33 Aim 3 will probe the circuits involved in nicotine receptor modulation of cocaine self-administration. R33 Aim 4 will use a biophysical approach to examine the novel hypothesis that cocaine has direct acute and long-term interactions with nicotine receptors. Together, these AIMs will help us understand how nicotine receptor activity modulates cocaine intake. Associated neurobiological mechanisms will be identified, potentially leading to novel approaches to treat tobacco and/or cocaine dependence.