This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Trace Amine-Associated Receptor 1 (TAAR1) is a receptor that directly responds to endogenous monoamines as well as amphetamine-related psychostimulants, including methamphetamine. Our recent data strongly suggests that TAAR1 may be critically important with regard to amphetamine-like psychostimulant action in brain, as it is found in monoaminergic brain regions, is co-localized in a subset of dopamine neurons with the dopamine transporter, and its direct activation by methamphetamine regulates dopamine transporter-mediated uptake and efflux of [3H]dopamine in vitro. We have found that TAAR1 is also expressed in immune cells, where it may play a major role in mediating immunological consequences of psychostimulant drug use, particularly methamphetamine use. We are assessing TAAR1 as a candidate target for novel psychostimulant addiction therapeutics by determining the effects of psychostimulant activation of TAAR1 in brain tissue derived from TAAR1 knockout and control mice ex vivo, and in cell lines that endogenously express TAAR1 in vitro. We are also identifying the phenotype of mouse and rhesus monkey immune cells that express TAAR1 and the role of the receptor in mediating methamphetamine effects on immune cells. At all three levels, we are creating an integrated assay platform to assess whether candidate TAAR1-directed compounds, selected on the basis of leads generated in our lab, can attenuate methamphetamine-induced effects. Accordingly, our purpose in defining psychostimulant-induced, TAAR1-mediated effects on brain monoaminergic function, drug-induced behaviors, and immune system response is to establish a new strategic approach to the medical management of psychostimulant addiction, particularly for the epidemic of methamphetamine addiction.
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