One serious consequence of chronic high dose methamphetamine abuse is the induction of a paranoid psychosis syndrome that frequently includes violent, impulsive and destructive behaviors. However, little clinical or preclinical research has been specifically directed at elucidating the processes and mechanisms that may be implicated in this methamphetamine-induced state. Our proposed research utilizes a newly developed dynamic infusion methodology and an escalating dose methamphetamine self-administration paradigm for simulating in rats the methamphetamine exposure conditions most frequently associated with the induction of the stimulant-induced psychosis syndrome, in order to critically assess the hypothesized role of changes in regional dopamine transmission and behavioral dynamics during the course of multiple methamphetamine binge exposures. Specific studies are designed to test our hypotheses that (1) during the course of multiple binge exposures a unique neurobiological profile emerges, outwardly characterized by a pronounced decrease in the amount of time spent engaged in stereotyped behaviors, and by the occurrence of frequent episodes of ambulatory bursting. Methamphetamine pharmacokinetics will be determined to assess whether subsequent adjustments to the treatment procedure are required, as well as to accurately interpret behavioral and mechanistic difference between treatment groups;(2) the emergent profile will be associated with increased aggressive behavior, enhanced startle reactivity and disrupted pre-pulse inhibition;(3) exposure to multiple methamphetamine binges will selectively down-regulate dopamine D2 and striatal D1 receptors, but will up- regulate cortical and accumbens dopamine D1 receptors. Differential effects of chronic methamphetamine on these receptor populations should also result in post-synaptic adaptations, at least in part, reflected in increased accumulation of the transcription factor, ?FosB in both the direct and indirect striatal pathways;(4) corresponding to the progressive development of the emergent profile, the methamphetamine-induced extracellular dopamine response will be significantly reduced in the caudate-putamen, whereas the dopamine response will be relatively unchanged or augmented in specific mesolimbic-cortical regions, including the nucleus accumbens and frontal cortex;(5) the ability to rapidly induce the emergent behavioral profile with subsequent methamphetamine binge challenge will persist for at least 30 days after discontinuation of the chronic, multi-binge treatment;potential mechanisms necessary for the expression of this behavioral syndrome will exhibit a parallel time course. The studies designed within the context of these Specific Aims should facilitate the development of a preclinical model of the stimulant-induced psychosis syndrome and the identification of potential mechanisms implicated in the qualitative changes in behavioral dynamics which emerge during chronic binge exposures.
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