Adolescence is a stage of development that in humans is often associated with increased levels of risk-taking and reckless behaviors. Furthermore, brain development underlying motivation and decision making processes makes this age period particularly vulnerable with respect to impulse control and the development of addiction. Therefore, the objective of this competitive renewal is to develop an effective pharmacologic treatment regimen for cocaine and/or methamphetamine addiction using S-(+)-gamma-vinyl GABA (GVG) in adolescent animals, a notably vulnerable population. Currently, no effective pharmacologic treatments are available for these indications in any population regardless of age. Thus, in addition to identifying effective treatment regimens, studies in this application will establish whether these regimens need to be modified in adults as the consequence of an adolescent drug history. Using a strategy similar to the one currently funded for racemic GVG, these studies will be targeted in several new directions. First, using adolescent animals, studies will identify an effective treatment regimen using the new molecular entity, S-(+)-GVG, the pharmacologically active enantiomer of GVG. Next, studies will determine if this regimen is effective once these animals reach adulthood and whether it remains effective in adult animals with an adolescent drug history of cocaine or methamphetamine exposure. These studies will use micro-PET imaging with 11C-raclopride as an independent measure of cocaine or methamphetamine-induced reward (increases in brain dopamine) and 18-FDG to identify glucose metabolic changes in dopaminergic and non-dopaminergic brain regions. Preliminary results demonstrate that all the proposed experiments can be completed as detailed. Ultimately, these data will be targeted towards the development of S-(+)-GVG for the treatment of cocaine and/or methamphetamine addiction in adolescence. Finally, these studies will determine if drug exposure during adolescence alters the adult therapeutic response to S-(+)-GVG.
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