Genetic deletion of trace-amine associated receptor 9 (TAAR9) in rats leads to decreased blood cholesterol levels

In the last two decades, interest has grown significantly in the investigation of the role of trace amines and their receptors in mammalian physiology and pathology. Trace amine-associated receptor 9 (TAAR9) is one of the least studied members of this receptor family with unidentified endogenous ligands and an unknown role in the central nervous system and periphery. In this study, we generated two new TAAR9 knockout (TAAR9-KO) rat strains by CRISPR-Cas9 technology as in vivo models to evaluate the role of TAAR9 in mammalian physiology. In these mutant rats, we performed a comparative analysis of a number of hematological and biochemical parameters in the blood. Particularly, we carried out a complete blood count, erythrocyte osmotic fragility test, and screening of a panel of basic biochemical parameters. No significant alterations in any of the hematological and most biochemical parameters were found between mutant and WT rats. However, biochemical studies revealed a significant decrease in total and low-density lipoprotein cholesterol levels in the blood of both strains of TAAR9-KO rats. Such role of TAAR9 in cholesterol regulation not only brings a new understanding of mechanisms and biological pathways of lipid exchange but also provides a new potential drug target for disorders involving cholesterol-related pathology, such as atherosclerosis

Tryptophan hydroxylase 2 genotype determines brain serotonin synthesis but not tissue content in C57Bl/6 and BALB/c congenic mice

10.1016/j.neulet.2010.06.035Neuroscience Letters48116-11NELE

Increased context-dependent conditioning to amphetamine in mice lacking TAAR1

Given the recent evidence indicating that amphetamine derivatives may also act as direct agonists of the G protein-coupled trace amine-associated receptor 1 (TAAR1), we hypothesized that TAAR1 could contribute to the reinforcing and addictive properties of amphetamines. Accordingly, the present study aimed to investigate the role of TAAR1 in the effects of psychostimulants by analyzing context-dependent sensitization and conditioned place preference (CPP) to d-amphetamine (AMPH) in TAAR1-KO mice. In context-dependent sensitization experiment, TAAR1-KO mice showed higher conditioned locomotor responses compared to wild-type mice. In the CPP test, TAAR1-KO animals were also more sensitive to priming-induced reinstatement of AMPH-induced conditioned place preference (CPP) than wild type mice. Importantly, saline-treated and AMPH-treated mice lacking TAAR1 demonstrated significant alterations in the total levels and phosphorylation of the critical subunit of NMDA glutamate receptors, GluN1, in the striatum, suggesting a role of TAAR1 in the modulation of frontostriatal glutamate transmission; this effect could underlie the observed alterations in conditioning processes. In conclusion, our data suggest that TAAR1 receptors play an inhibitory role with respect to conditioned responses to AMPH by modulating, at least in part, corticostriatal glutamate transmissio

Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice

10.1021/cn300127hACS Chemical Neuroscience4184-8

Overexpression of alpha-synuclein following methamphetamine: is it good or bad?

alpha-Synuclein is a presynaptic protein involved in various degenerative disorders now defined as synucleinopathies. These include neurological diseases that share a few pathological features consisting of aggregates of both normal and altered alpha-synuclein within specific neuronal populations and/or glial cells. The prototype of synucleinopathies is represented by Parkinson's disease (PD) in which alpha-synuclein is identified as a constant component of neuronal pale eosinophilic inclusions: "the Lewy Bodies." In the present article, we discuss the potential significance of amphetamine-induced overexpression of alpha-synuclein in light of clinical findings showing neurodegeneration following overexpression of alpha-synuclein and recent experimental studies that measured increased expression of alpha-synuclein following amphetamine derivatives