Taar1 gene variants have a causal role in methamphetamine intake and response and interact with Oprm1

eLife

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[1] Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, United States;Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, United States;Veterans Affairs Portland Health Care System, Portland, United States;Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, United States;Veterans Affairs Portland Health Care System, Portland, United States;Department of Psychiatry, Oregon Health & Science University, Portland, United States;Department of Genetics, Genomics and Informatics, University of Tennessee Health Sciences Center, Memphis, United States;Division of Neuroscience, Oregon National Primate Research Center, Portland, United States;Transgenic Mouse Models Shared Resource, Knight Cancer Institute, Oregon Health & Science University, Portland, United States;

关键词: trace amine-associated receptor 1;    mu-opioid receptor;    CRISPR-Cas9;    self administration;    hypothermia;    addiction;    Mouse;   

DOI  :  10.7554/eLife.46472

来源: publisher

【 摘 要 】

10.7554/eLife.46472.001We identified a locus on mouse chromosome 10 that accounts for 60% of the genetic variance in methamphetamine intake in mice selectively bred for high versus low methamphetamine consumption. We nominated the trace amine-associated receptor 1 gene, Taar1, as the strongest candidate and identified regulation of the mu-opioid receptor 1 gene, Oprm1, as another contributor. This study exploited CRISPR-Cas9 to test the causal role of Taar1 in methamphetamine intake and a genetically-associated thermal response to methamphetamine. The methamphetamine-related traits were rescued, converting them to levels found in methamphetamine-avoiding animals. We used a family of recombinant inbred mouse strains for interval mapping and to examine independent and epistatic effects of Taar1 and Oprm1. Both methamphetamine intake and the thermal response mapped to Taar1 and the independent effect of Taar1 was dependent on genotype at Oprm1. Our findings encourage investigation of the contribution of Taar1 and Oprm1 variants to human methamphetamine addiction.

【 授权许可】

CC BY