The role of various risk factors in relapse with methamphetamine (METH) dependence remains to bedetermined. METH poses unique challenges, in that it's highly addictive nature is compounded bycognitive deficits. The studies proposed in this project will study cue and drug induced relapse by using thereinstatement model of drug-seeking behavior in rats. The overarching goal of this project is to integratefindings from the animal model of relapse with the clinical projects in the TRAC that are focused on cuereactivity and cognitive dysfunction in METH-dependent humans. We propose the following specific aims:1) Demonstrate conditioned-cued and drug-primed reinstatement of METH-seeking. We predict that ratsthat have undergone chronic METH self-administration will show extinction of responding andreinstatement of METH-seeking behavior in the presence of discrete conditioned cues or after METHinjections. Furthermore, prolonged exposure to METH should result in resistance to extinction and agreater degree of drug-seeking at the time of reinstatement.2) Determine the cognitive deficits that arise from chronic METH.
This aim will begin with assessingdeficits in novel object recognition in rats with a history of chronic METH self-administration. We predictthat these deficits will be more severe in animals with greater drug-seeking. In addition, we predict thatpre-existing lesions of the orbitofrontal cortex will exacerbate cognitive deficits and METH-seeking. Duringthe course of the P20, as results in METH dependent human subjects are obtained in projects 2 and 4, wewill then apply additional cognitive testing procedures in rats that parallel those used in the humansubjects.3) Attenuate relapse and cognitive dysfunction with novel pharmacotherapies. We will test the possibilitythat facilitation of NMDA receptor function via glycine site modulation by d-cycloserine will facilitateextinction, reduce reinstatement, and improve cognitive performance. We also predict that the glutamateenhancing agents, N-Acetylcysteine and modafinil, will facilitate extinction and reduce reinstatement inanimals after METH self-administration and that these drugs will have co-modulating beneficial effects oncognitive deficits. Studies from this aim will give direction to clinical pharmacotherapy approaches inprojects 2 and 4, and provide ideas for site-selective drug delivery in project 1.These studies will provide a comprehensive examination of extinction, relapse, and cognitive deficitsafter chronic METH. In conjunction with the clinical projects, we will modify our experimental approachesas information is derived from human subjects. In turn, we will provide promising leads for the other TRACprojects in regards to pharmacotherapy (projects 2 and 4) or direct brain site injection (Project 1).
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