The potent stimulant of abuse, methamphetamine [METH] is highly addictive and chronic administrationof this drug can lead to tolerance to METH's effects. The goal of this proposal to elucidate the underlyingmechanisms of tolerance to METH that provide a transient resistance to toxicity resultant to multiple highdoseadministration. Similar mechanisms may underlie the resistance of adolescent rodents to METHtoxicity. Several factors have been identified that appear to be closely linked to the persistent DA deficits inthe striatum caused by multiple administrations of high doses of METH. Utilizing evidence from selectedmarkers (e.g. the dopamine transporter [DAT], vesicular monoamine transporter-2 [VMAT-2] function, DATcomplex formation, glial cell reactions, heat shock protein expression, and nitrogen-dependent reactivespecies production), these factors appear to fall into two broad classifications with respect to their temporalrelationship to METH exposure. These include: a 'first stage' that persists for ~ 8 hours after the METHtreatment, and 2) a 'second stage' that appears to occur from ~24-48 hrs. Our studies will examine theoverall hypothesis: Exposure to escalating doses of METH leads to a temporary alteration in mechanismsthat trigger Stage 2 after Stage 1 expression, thereby preventing occurrence of METH-induced toxicity.The following Specific Aims are designed to prove or disprove this hypothesis: (I): Determine the effectsand temporal profile of a tolerance-inducing METH pretreatment on nigrostriatal DA systems per se, and theresponse of Stages 1 and 2 to subsequent challenge with multiple high-dose METH administrations; (II)Determine the effects of a tolerance-inducing METH pretreatment on the expression of oxidatively linkedsystems per se, and their response in Stages 1 and 2 to subsequent challenge with multiple high-doseMETH administrations. (Ill) Determine the effects of a tolerance-inducing METH pretreatment on DA,glutamate and glucocorticoid systems per se, and their response in Stages 1 and 2 to subsequent challengewith multiple high-dose METH administrations. The data obtained from the experiments in each of theseSpecific Aims will increase our understanding of the neurochemistry involved in the development of toleranceto METH. In addition, together with experiments in adolescent animals, these data will provide insight intoissues related to drug abuse vulnerability in the adolescent population.
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