COBRE: UMMC: ROLE OF MU-OPIOID SYSTEM IN METHAMPHETAMINE SENSITIZATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Methamphetamine is currently one of the most widely abused drugs in the United States. Long term use of the drug may produce behavioral sensitization. The mesolimbic dopamine system in the central nervous system is thought to play a critical role in the development of behavioral sensitization. However, dopamine activity receives regulation from other transmissions and the existence of close interactions among opioidergic, gamma-aminobutyric acid (GABA)ergic, and dopaminergic neurons in the mesolimbic pathway is well established. The mu-opioid system may modulate dopamine activity via GABA-containing neurons. It is known that amphetamine induces release of endogenous opioid peptides and an increase in extracellular dopamine in the mesolimbic system. Opioid receptor antagonists can prevent amphetamine-induced dopamine and behavioral hyperactivity. Therefore, we hypothesized that mu-opioid system is involved in the development of methamphetamine sensitization through modulation of GABA and dopamine systems. To test the hypothesis and to clarify the role of mu-opioid system in methamphetamine sensitization, we plan to use mu-opioid receptor knockout mice to detect changes in behaviors and neurochemicals (opioidergic, dopaminergic, and GABAergic activity) during the development of methamphetamine sensitization. For a better understanding of the interactions among opioidergic, GABAergic, and dopaminergic systems in the development of methamphetamine sensitization, pharmacological manipulations on these systems will be used in the study.