The incidence of the combined use of cocaine and ethanol has been increasing for several years. In emergency departments around the country, increasing time and millions of dollars is spent on the treatment of acute intoxication traumatic injuries caused by impaired judgement, and chronic medical problems caused by use of these substances. The development of neuropharmacological agents that will reduce craving and lead to abstinence, is the ultimate goal. This is a proposal for the M.R.S.D.A.(KO1) which would develop the applicant's skill in studying the effects of substances of abuse on the brain, specifically dopaminergic neurons of the ventral tegmental area (VTA), which are important for drug-induced reward. Didactic instruction (graduate level courses), supervised literature review, and mentored research experience will provide the groundwork for the long-term goal of studying the interaction of substance abuse in the brain. In the research project, the applicant will master various electrophysiological techniques to evaluate the actions of ethanol in combination with cocaine or cocaethylene, on VTA neurons. The applicant, an emergency physician, has experience in treating the sequelae of substance abuse. To develop as a independent scientist, he will combine this clinical experience with studies of the neuroelectrophysiological mechanisms underlying substance abuse. These studies will build upon observations made in his mentor's laboratory, that serotonin enhances the action of dopamine and ethanol on dopaminergic VTA neurons, which mediate drug-induced reward. Since cocaine blocks reuptake of serotonin as well as dopamine, the combination of cocaine and ethanol may act in a superadditive manner in the VTA to enhance reward. Changes in the firing rate of VTA neurons will be measured with extracellular recording in brain slices, in response to a) the combination of ethanol and cocaine, or ethanol and cocaethylene, b) the combination of cocaine and ethanol, or ethanol and cocaethylene, in the presence of the dopamine D2 antagonist sulpiride, the serotonin 5-HT2 antagonist ketanserin, the GABAB antagonist saclofen and the serotonin 5-HT1B antagonist cyanopindolol. Changes in the spike afterhyperpolarization will be measured with intracellular recording in response to a) ethanol and cocaine, or ethanol and cocaethylene and b) these combinations in the presence of the serotonin 5-HT2 antagonist ketanserin. This KO1 award would free the applicant from clinical responsibility and permit sufficient time for his development as a basic research scientist/clinician.
