Project 1 will evaluate the role of corticolimbic circuitry in extinction training and cue- andmethamphetamine-induced reinstatement of drug-seeking in animals trained to self-administermethamphetamine using both a short and long access treatment protocol. It is hypothesized that thecognitive impairment that has been well documented in methamphetamine addicts will be manifested in thisrat model as deficits in extinction training. Further, poor extinction learning in animals trained on a longaccess methamphetamine protocol will arise from the fact that the prefrontal cortex, which is normallyengaged by extinction training, is impaired and therefore no longer able to regulate the reinstatement ofdrug-seeking. Thus, the lack of prefrontal involvement is hypothesized to exacerbate reinstatementresponding to both a previously associated Pavlovian conditioned cue and a noncontingent injection ofmethamphetamine. This basic protocol for methamphetamine self-administration, extinction andreinstatement will be developed in collaboration with Project 3 that will use this protocol to examinecognitive effects of methamphetamine self-administration. Also, circuitry maps generated in Project 1 willbe integrated with neuroimaging data obtained from methamphetamine addicts in Project 2 who willundergo analogous procedure of cue-induced drug interest and subsequent extinction of the cue-inducedresponse. Finally, Projects 3 and 4 will examine the effects of putative cognitive enhancers, Nacetylcysteine,D-cycloserine and modafinil in both the animal model of methamphetamine extinction andreinstatement and in methamphetamine addicts. Positive effects in projects 3 or 4 will then be integratedwith the present project to determine where in the brain these drugs may be ameliorating addiction-relatedbehaviors. Based upon the hypothesis that methamphetamine-induced deficits in prefrontal corticalfunction inhibit extinction learning and exacerbate the reinstatement of drug-seeking, it is anticipated thatany effect of systemic treatment with cognitive enhancers identified in Projects 3 or 4 will be replicated bymicroinjecting the drug directly into the prefrontal cortex.By identifying sites of action in the brain by drugs capable of ameliorating methamphetamine addiction,future proteomic and in vivo multiphoton neuroimaging can be more efficiently targeted to sites of drugaction within the brain, and to identify new cellular targets for future improvements in pharmacotherapiesfor methamphetamine addicts.
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