The potent stimulants of abuse as methamphetamine (METH) and cocaine (COC) are highly addictive compounds and encourage frequent persistent use. With chronic administration of these drugs, tolerance occurs which compounds and encourage frequent persistent use. With chronic administration of these drugs, tolerance occurs which leads to the use of particularly large quantities; this frequently leads to consequent escalation of psychotic, violent behavior, seizure initiation and other serious sequelae. The goal of this proposal is to elucidate and characterize those factors which influence the development of tolerance to METH and determine if changes and either metabolism of METH or CNS active transport are responsible for the phenomenon of tolerance. Our studies will examine the overall hypothesis: A tolerance-inducing pretreatment with METH causes a significant shift in the distribution patterns of this hypothesis: A tolerance-inducing pretreatment with METH causes a significant shift in the distribution patterns of this drug after subsequent METH challenges; however, cocaine pretreatment does not cause a similar phenomenon. Three Specific Aims are proposed: (1) Identify the factors necessary for the induction of tolerance; (b) characterize disposition factors affecting the development of METH tolerance; and (c) investigate the possibility of cross-tolerance with other CNS stimulants, such as cocaine (COC). In Specific Aim A, experiments are designed elements of METH are critical for induction and persistence of tolerance. Experiments for Specific Aim B will determine if METH pretreatment causes a shift in the active transport mechanisms for this stimulant. Finally, experiments for Specific Aim C will combine METH, COC or MDMA pretreatment, followed by challenge to determine the selectivity of the tolerance response. Our proposed studies will use a rat model for METH tolerance developed previously in the laboratory of Drs. Hanson and Gibb; moreover, mice genetically modified for expression of P-glycoproteins will also be used. The studies proposed will elucidate the nature of tolerance caused by METH, as well as identify the circumstance or type of METH exposures likely to cause this phenomenon. In addition, the results from this Project will elucidate the dynamic pharmacokinetic processes that determine the distribution of METH and related stimulants and help predict the consequences of various patterns of stimulant abuse.