METHAMPHETAMINE EFFECTS VIA TRACE AMINE ASSOCIATED RECEPTOR 1

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In the brain, monoamine transporters for dopamine, norepinephrine and serotonin play key roles in clearance of the cognate neurotransmitters released into the synaptic space which is essential for appropriate neural function of monoaminergic activity. Methamphetamine, a widely abused and highly addictive psychostimulant drug, interferes with these transporters to elevate the levels of neurotransmitters in the synaptic clefts, which results in immediate and long-term changes associated with psychostimulant effects and addiction of methamphetamine. Trace amine-associated receptor 1 (TAAR1) is widely expressed in brain monoaminergic nuclei, and recent studies have established that this receptor serves as a monoaminergic modulator in the brain. Methamphetamine can activate TAAR1 in vitro and its interaction with TAAR1 decreases dopamine uptake, induces dopamine efflux, and triggers dopamine transporter internalization in brain striatum. This indicates a correlation between TAAR1 signaling and methamphetamine action on the dopamine transporter. Methamphetamine is a transporter substrate thought to function through direct interaction with monoamine transporters. Our studies are uncovering new mechanisms that underlie the role of TAAR1 in methamphetamine influence on monoamine transporters, which may advance the understanding of methamphetamine addiction and promote new therapeutics for such disorder.