Neurochemical Substrates of Sedative/Hypnotic Action:Proton MRS Studies

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DESCRIPTION (provided by applicant): This proposal describes experiments aimed at understanding the neurochemical substrates of sedative/hypnotic action. Benzodiazepines are sedative/hypnotics that work through the GABAA receptor, they are often prescribed to treat anxiety (i.e. alprazolam), and they are abused by individuals with a history of abusing alcohol, opiates, or sedatives. Newer benzodiazepine-like compounds also modulate the GABAA receptor in a more selective manner, they are typically prescribed to treat insomnia (i.e. zolpidem), and they are believed to have reduced abuse potential compared to their less selective benzodiazepine counterparts. However, despite their differential interactions with the GABAA receptor and their different behavioral effects compared to conventional benzodiazepines, they do share in common the potential to be abused. Zolpidem in particular is abused at high doses. These experiments will test the hypothesis that the different subjective (anxiolytic, reinforcing, and/or sedative) effects of therapeutic doses of alprazolam and zolpidem are associated with distinct neurochemical profiles, while a higher dose of zolpidem loses its selectivity and resembles alprazolam with respect to subjective effects (i.e., it becomes more anxiolytic and/or reinforcing) and neurochemistry. These experiments will employ proton magnetic resonance spectroscopy (1H MRS) at 4 Tesla in conjunction with subjective questionnaires in order to investigate the changes in brain metabolite concentrations resulting from acute oral administration of alprazolam or zolpidem in drug-experienced volunteers. Comparing the effect of alprazolam or zolpidem on brain levels of GABA, glutamate, glutamine, etc., could have serious implications for drug development strategies focusing solely on receptor selectivity if they do indeed support the hypothesis that the neurochemical mechanisms associated with the reinforcing effects of sedative/hypnotics are the common final pathway to influence abuse liability. PUBLIC HEALTH RELEVANCE: Approximately 10% of the population suffers from some type of anxiety disorder, while close to 30% of the population reports difficulty sleeping. Current sedative/hypnotic treatments are effective short- term solutions, but are accompanied by side effects that limit their clinical utility, such as abuse potential. The experiments proposed in this application are aimed at understanding the neurochemistry that underlies the reinforcing effects of this class of drugs in order to contribute to the research focused on separating the clinically useful effects of sedative/hypnotics from their abuse potential.