Trace amines, distinguishable from the well-characterized biogenic amines, have been known to exist in mammalian brain for over 25 years. The recent discovery of a family of mammalian trace amine receptors (TARs) presents a significant new resource for exploring the physiological and pharmacological relevance of trace amines in brain (Borowsky et al, 2001). In conjunction with this finding is the unanticipated discovery that drugs of abuse, ranging from amphetamine, MDMA, LSD, as well as dopamine stimulate rat TAR1-mediated cAMP formation at pharmacologically relevant concentrations (Bunzow et al, 2001). Accordingly, trace amine receptors may directly or indirectly contribute to psychostimulant and hallucinogenic drug effects. As human and rodent trace amine receptors diverge in structure, subtype number and brain distribution, we postulate that non-human primates will provide a more suitable model for uncovering the physiological and pharmacological relevance of trace amine subtypes. In this regard, pilot studies indicate a 96% sequence identity for TAR1 in non-human primate and human. To establish fundamental information needed to explore TAR subtype function, we will investigate non-human primate TAR subtype structure, pharmacology, signal transduction and brain distribution.
Aim 1 will determine whether human TAR subtypes (TAR1, 3, 4, 5) and structurally related orphan receptors (GPR57, GPR58 and PNR) exist in nonhuman primates. Based on these results, Aim 2 will utilize luciferase assays sensitive to different signal transduction pathways to uncover agonists as well as antagonists that block agonist-induced receptor activation. To characterize the pharmacological profile of these receptors, radioreceptor assays will be developed from lead compound(s) identified from luciferase assays.
Aim 3 will map TAR subtype mRNA and protein distribution in primate brain using in situ hybridization, real-time RT-PCR and immunohistochemistry, to discern which receptor subtypes are expressed in brain for further exploration. Our pilot studies suggest that primate TARs are direct targets of psychostimulant drugs of abuse in brain. The proposed studies will form the basis for investigating the physiological and pharmacological relevance of trace amine receptors in a primate model, and may provide novel leads for developing therapeutic agents to treat addiction and possibly neuropsychiatric disorders. ? ? ?
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