Trace amine-associated receptor 1 modulates dopaminergic activity
ABSTRACT The recent identification of the trace amine-associated receptor (TAAR)1 provides an opportunity to dissociate the effects of trace amines on the dopamine transporter from receptor-mediated effects. To separate both effects on a physiological level, a Taar1 knockout mouse line was generated. Taar1 knockout mice display increased sensitivity to amphetamine as revealed by enhanced amphetamine-triggered increases in locomotor activity and augmented striatal release of dopamine compared with wild-type animals. Under baseline conditions, locomotion and extracellular striatal dopamine levels were similar between Taar1 knockout and wild-type mice. Electrophysiological recordings revealed an elevated spontaneous firing rate of dopaminergic neurons in the ventral tegmental area of Taar1 knock-out mice. The endogenous TAAR1 agonist p-tyramine specifically decreased the spike frequency of these neurons in wild-type but not in Taar1 knockout mice, consistent with the prominent expression of Taar1 in the ventral tegmental area. Taken together, the data reveal TAAR1 as regulator of dopaminergic neurotransmission.
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ABSTRACT: Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, play also an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high order cognitive processes. TAAR1 selective ligands have shown potential antipsychotic, antidepressant and pro-cognitive effects in experimental animal models; however, it remains unclear if TAAR1 can affect PFC-related processes and functions. In this study, we document distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions.Neuropsychopharmacology accepted article preview online, 09 March 2015. doi:10.1038/npp.2015.65.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2015; DOI:10.1038/npp.2015.65 · 7.83 Impact Factor
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ABSTRACT: The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.
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ABSTRACT: Introgression of genetically engineered modifications (GMs) into natural populations represents a new realm for mutation theory. GMs, like mutations, have direct and pleiotropic impacts that can disrupt evolved adaptive suites. If GM males are more competitive or attractive mates, the “Trojan Gene Hypothesis” predicts potentially drastic impacts. We examined sexual selection in transgenic growth hormone (Tg) mice that are strong Trojan candidates given their exceptional size and extensive pleiotropic deficits. We hypothesized that the sophisticated olfactory abilities of females would recognize dysregulation of Tg males (the Transparent Genome Hypothesis). Females expressed interest in Tg males and their volatile scent, but when allowed nasal contact with urine (critical to mate choice) they preferred normal males. Tg male urine had reduced major urinary proteins (important in social signaling) and contained albumin and transferrin indicative of pathology. Novel Tg males failed to elicit pregnancy block in recently inseminated females (the “Bruce Effect”) whereas normal males were highly effective. Normal males expressed high aggression but Tg males were placid, non-aggressive and were largely ignored by normal males. Female mice also strongly preferred normal males over p53± knockout males in response to volatiles, contact with urine and male presence. This study suggests that conspecific discrimination of fitness may be more powerful than generally appreciated. This has great implications for introductions of GM animals and sexual selection generally.Evolutionary Biology 06/2013; 41(2):276-298. DOI:10.1007/s11692-013-9268-x · 3.27 Impact Factor