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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
μ-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 μ-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 μ-opioid
system in methamphetamine sensitization, we plan to use
μ-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.
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