<i>Taar1</i> gene variants have a causal role in methamphetamine intake and response and interact with <i>Oprm1</i>.

Abstract

We 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, <i>Taar1</i>, as the strongest candidate and identified regulation of the mu-opioid receptor 1 gene, <i>Oprm1</i>, as another contributor. This study exploited CRISPR-Cas9 to test the causal role of <i>Taar1</i> 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 <i>Taar1</i> and <i>Oprm1</i>. Both methamphetamine intake and the thermal response mapped to <i>Taar1</i> and the independent effect of <i>Taar1</i> was dependent on genotype at <i>Oprm1</i>. Our findings encourage investigation of the contribution of <i>Taar1</i> and <i>Oprm1</i> variants to human methamphetamine addiction.