TAAR1 POLYMORPHISMS IN RHESUS MONKEYS

Harvard Medical School, Boston MA

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Abstract

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. Rhesus monkey Trace Amine-Associated Receptor 1 (TAAR1) responds to a wide spectrum of endogenous amines (including the "trace" amines betta-phenylethylamine and tyramine, and the common biogenic amines dopamine, norepinephrine and serotonin), as well as amphetamine-like psychostimulants, including methamphetamine. In rhesus monkey brain, we have shown that TAAR1 mRNA is expressed in monoaminergic regions, and that TAAR1 is co-expressed with and modulates monoamine transporters in monoaminergic neurons. Our studies have demonstrated that TAAR1 is activated along with monoamine autoreceptors by the common biogenic amines, but that only TAAR1 is activated by methamphetamine, resulting in aberrant cAMP accumulation, triggering of cellular phosphorylation events and a consequent deregulation of monoamine transporter kinetic function. We have also recently found that TAAR1 is expressed at substantially high levels in rhesus monkey and human immune cells where it may mediate methamphetamine-induced effects on the immune system and in this regard, may play a role in methamphetamine-associated effects on human and simian immunodeficiency virus infectivity and disease progression. The emerging importance of this receptor in modulating brain monoamine systems and potentially immune cell function provides a strong rationale for determining whether polymorphic variation at the locus is functional and examining the significant similarities between human and rhesus monkeys. In this grant we apply our laboratory's significant expertise in assessing TAAR1 function, polymorphism discovery in rhesus monkey genes associated with drug addiction and neuropsychiatric disorders, and genetic variant functional assessments to initiate investigation of the TAAR1 locus. We will identify and assess functionality of the novel genetic polymorphisms in both the rhesus monkey and human TAAR1 locus to determine whether TAAR1 polymorphisms could contribute to the genetic variability that underlies susceptibility to and/or protection from neuropsychiatric and drug addiction disorders, and potentially, methamphetamine effects on the immune system. This is a completely novel area in which no investigations have been reported, and our preliminary data verifies the existence of polymorphisms in the rhesus monkey TAAR1 locus.