fMRI Studies Investigating the Choice Effects of Sedative/Hypnotics

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DESCRIPTION (provided by applicant): This is a request for 4 years of funding through the "Mentored Research Scientist Development Award" (K01) mechanism. The applicant, a behavioral pharmacologist with experience using rodent and nonhuman primate models of drug abuse, proposes a program of training in human clinical pharmacology and magnetic resonance imaging. The long-term goal of the applicant is to become an independent and translational investigator, skilled in the application of magnetic resonance methods for the study of substance abuse research. The training plan includes didactic coursework in MR technology and experimental design, workshops, laboratory rotations, ongoing training in the responsible conduct of research, attendance at both drug abuse and brain imaging scientific meetings, and interactions with the IRB and FDA. The research component of this award has been carefully designed to parallel the training plan and is aimed at understanding the neural substrates of benzodiazepine (BZ) action. For each training goal there is a corresponding research directive that will allow the candidate the opportunity to implement newly developed skills. The experiments outlined in this proposal will use functional magnetic resonance imaging (fMRI) in order to characterize the neural circuitry underlying the drug vs. money choice effects induced by BZs in drug-experienced individuals. The first set of studies will be undertaken in the laboratory to determine the detailed time course of the subjective and choice effects of orally administered alprazolam and zolpidem. The second set of studies will be undertaken in the magnet to determine the optimal parameters for measuring BZ-induced changes in cerebral hemodynamic response following acute oral administration of alprazolam and zolpidem. The third set of studies will compare the subjective effects, as well as the hemodynamic response associated with the drug vs. money choice effects, produced by the anxiolytic drug alprazolam to those of the popular sleep-aid zolpidem. Examining the drug-induced patterns of brain activation of these medications will lead to a better understanding of why alprazolam is readily abused, while zolpidem is not. These studies will contribute to the overarching goals of the field, which has been focused on determining how BZs mediate their behavioral effects in an effort to separate the clinically useful effects from their abuse potential.