TY - JOUR TI - Taar1 gene variants have a causal role in methamphetamine intake and response and interact with Oprm1 AU - Stafford, Alexandra M AU - Reed, Cheryl AU - Baba, Harue AU - Walter, Nicole AR AU - Mootz, John RK AU - Williams, Robert W AU - Neve, Kim A AU - Fedorov, Lev M AU - Janowsky, Aaron J AU - Phillips, Tamara J A2 - Dulac, Catherine A2 - Flint, Jonathan A2 - Baud, Amelie A2 - Yamamoto, Bryan VL - 8 PY - 2019 DA - 2019/07/05 SP - e46472 C1 - eLife 2019;8:e46472 DO - 10.7554/eLife.46472 UR - https://doi.org/10.7554/eLife.46472 AB - 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, 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. KW - trace amine-associated receptor 1 KW - mu-opioid receptor KW - CRISPR-Cas9 KW - self administration KW - hypothermia KW - addiction JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -