Naltrexone and alprazolam-induced fMRI changes

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DESCRIPTION (provided by applicant): The long-term career goal of the applicant is to become an independent, interdisciplinary researcher applying functional magnetic resonance imaging (FMRI) to the study of alcohol related disorders. This application proposal includes two components: formal training in MR technology, statistical analysis and medical ethics and a specific research project defined below. Background: Alcoholism is a multifactorial disorder associated with tremendous individual disability and enormous cost to society. Naltrexone is an opioid blocker recently approved for the treatment of alcoholism. Increased understanding of the neurobiologic effects of naltrexone is needed to maximize the effectiveness of this drug and to plan for new pharmacologic treatments. The mood enhancing effects of a benzodiazepine challenge can serve as a probe to study the effects of naltrexone on alcohol-induced mood enhancement and cerebral function. This protocol will use Dynamic Susceptibility Contrast Magnetic Resonance Imaging (DSC MRI) to address these issues. Method: This project will study 20 abstinent individuals with a personal history of alcohol dependence and 20 comparison subjects over a five-year period. Each group will participate in a double blind, placebo-controlled, counterbalanced, crossover design protocol. Subjects will be pre-treated with naltrexone or placebo before receiving a challenge of alprazolam or placebo. This will result in 4 treatment conditions: placebo-placebo, placebo-alprazolam, naltrexone- placebo, and naltrexone-alprazolam. Each subject will participate in four scanning sessions, one for each treatment condition. Each scanning session will include a series of three scans. The following hypotheses will be tested: Hypothesis 1: There will be an interaction between the pretreatment conditions and the challenge conditions such that 1 a) When an alprazolam challenge is given to alcoholics unopposed, the rate of RCBV decrease will be greatest and l b) pretreatment with naltrexone will significantly slow the rate of rCBV decrease; Hypothesis 2: Alprazolam will produce greater mood-enhancement in alcoholics compared to normal controls, as measured by established mood scales; Hypothesis 3: Naltrexone will attenuate alprazolam's mood enhancing properties; Hypothesis 4: A rapid decrease in rCBV will correlate with reports of mood-enhancement. Pretreatment with naltrexone will correlate with a slower decrease in rCBV and less mood-enhancement than when alprazolam is given unopposed.