This MRSDA K0l application requests support to promote the candidate's development into an independent investigator in the application of positron emission tomography (PET) and single photon emission tomography (SPECT) neuroimaging methods to the neurochemistry of alcohol and nicotine dependence. The candidate's proposed Career Development and Research Plans will be facilitated by ongoing mentoring relationships with Drs. Stephanie O'Malley and Robert B Innis, established senior scientists with internationally recognized accomplishments in clinical neuropsychopharmacology of alcohol dependence and PET and SPECT imaging, respectively. A comprehensive five-year Career Development Plan will provide the candidate with the multi- disciplinary skills required to ultimately lead an independent and highly productive research program in brain imaging of substance dependence. This plan has been carefully devised to satisfy specific career development needs in the following major areas: l) clinical research methods in alcoholism; 2) use of radioisotopes in humans; 3) imaging instrumentation and analysis; 4) radiotracer development, pharmacokinetic and tracer kinetic modeling; and 5) quantitative skills and biostatistics. Formal training in these highly specialized areas will be achieved through an intensive curriculum of seminars, tutorials, extramural didactics, and research studies. Three specific aims are proposed which seek to assess the status of key dopaminergic and serotonergic synaptic markers in actively dependent alcoholic smokers and nonsmokers and nonalcoholic smokers and nonsmokers. We propose l) to determine if striatal DA transporters are decreased in alcoholics and to delineate the effects of nicotine in the alcoholic and nonalcoholic populations as assessed via SPECT using [123I]beta-CIT; 2) To determine if brainstem 5-HT transporters are elevated in actively dependent alcoholics and to distinguish the effects of nicotine in alcoholic and nonalcoholic populations, as assessed via SPECT using [123I]beta-CIT and 3) To determine if cortical 5HT2A receptors are differentially regulated in actively dependent alcoholic smokers and alcoholic nonsmokers as assessed via PET using [18F]deuteroaltanserin. The findings from these studies will offer insight into the neurochemical alterations associated with dual alcohol and nicotine dependence which may guide the development of more effective pharmacotherapies for these devastating brain disorders.