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

Alexandra M. Stafford, Cheryl Reed, Harue Baba, Nicole Ar Walter, John Rk Mootz, Robert W. Williams, Kim Neve, Lev Fedorov, Aaron Janowsky, Tamara Phillips

Research output: Contribution to journalArticle

1 Citation (Scopus)

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, 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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Jul 9 2019

Fingerprint

Methamphetamine
Genes
Clustered Regularly Interspaced Short Palindromic Repeats
Hot Temperature
Chromosomes, Human, Pair 10
Inbred Strains Mice
mu Opioid Receptor
Chromosomes
Animals
Genotype

Keywords

  • addiction
  • CRISPR-Cas9
  • genetics
  • genomics
  • hypothermia
  • mouse
  • mu-opioid receptor
  • neuroscience
  • self administration
  • trace amine-associated receptor 1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Taar1 gene variants have a causal role in methamphetamine intake and response and interact with Oprm1. / Stafford, Alexandra M.; Reed, Cheryl; Baba, Harue; Walter, Nicole Ar; Mootz, John Rk; Williams, Robert W.; Neve, Kim; Fedorov, Lev; Janowsky, Aaron; Phillips, Tamara.

In: eLife, Vol. 8, 09.07.2019.

Research output: Contribution to journalArticle

Stafford, Alexandra M. ; Reed, Cheryl ; Baba, Harue ; Walter, Nicole Ar ; Mootz, John Rk ; Williams, Robert W. ; Neve, Kim ; Fedorov, Lev ; Janowsky, Aaron ; Phillips, Tamara. / Taar1 gene variants have a causal role in methamphetamine intake and response and interact with Oprm1. In: eLife. 2019 ; Vol. 8.
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