Potential Role of Phasic Dopamine and Endocannabinoids in Conditioned Withdrawal

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 DESCRIPTION (provided by applicant): Of the 3 million people who used an illicit drug in 2010, 17.3% reported the non-medical use of pain relievers (2010 NSDUH); an alarming statistic, as nonmedical opioid abusers show a high prevalence to develop dependence (2 million in 2010), explore alternative routes of drug administration (e.g., intravenous), and seek out potentially dangerous opiate sources on the street. During a hallmark feature of opiate dependence, withdrawal, environmental stimuli become associated with a drug-induced negative emotional state and develop the power to modify natural reward seeking. The aims of this project are to elucidate how the opiate dependent brain computes behaviorally relevant stimuli during conditioned withdrawal and to identify pharmacotherapeutic approaches that alleviate these maladaptations. Previous studies indicate that the mesolimbic dopamine pathway is generally depressed during opiate withdrawal and systemically increasing endocannabinoids-known neuromodulators of mesolimbic function-reduce overt withdrawal symptomatology. However, it remains unknown how dopamine neurons represent transiently present withdrawal associated stimuli that are capable of suppressing reward seeking and how endocannabinoids improve withdrawal symptoms. Here we will monitor near real-time dopamine release events during conditioned withdrawal induced suppression of food seeking and further assess the potentially therapeutic effects of increasing distinct endocannabinoids within the mesolimbic pathway. The innovative nature of the experiments proposed herein will allow us to achieve an unprecedented analysis of mesolimbic pathway neuromodulation during conditioned opiate withdrawal. Combining a cutting-edge electrochemical technique-fast-scan cyclic voltammetry, drug microinfusions and operant behavior will allow, for the first time, a near real-time assessment of how dopamine computes environmental stimuli during conditioned withdrawal and whether endocannabinoids rectify suppressed mesolimbic function in opiate dependence. These results will elucidate a potentially interactive role of endocannabinoids and mesolimbic dopamine in conditioned withdrawal that may lead to the development novel pharmacotherapies to prevent relapse in opiate addicts.