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Major gene effects on traits associated with substance use disorders are rare. Previous findings in methamphetamine drinking (MADR) lines of mice, bred for high or low voluntary MA intake, and in null mutants demonstrate a major impact of the trace amine-associated receptor 1 ( Taar1 ) gene on a triad of MA-related traits: MA consumption, MA-induced conditioned taste aversion and MA-induced hypothermia. While inbred strains are fundamentally genetically stable, rare spontaneous mutations can become fixed and result in new or aberrant phenotypes. A single nucleotide polymorphism in  Taar1  that encodes a missense proline to threonine mutation in the second transmembrane domain ( Taar1   m1J  ) has been identified in the DBA/2J strain. MA is an agonist at this receptor, but the receptor produced by  Taar1   m1J   does not respond to MA or endogenous ligands. In the present study, we used progeny of the C57BL/6J × DBA/2J F2 cross, the MADR lines, C57BL/6J × DBA/2J recombinant inbred strains, and DBA/2 mice sourced from four vendors to further examine  Taar1 -MA phenotype relations and to define the chronology of the fixation of the  Taar1   m1J   mutation. Mice homozygous for  Taar1   m1J   were found at high frequency early in selection for high MA intake in multiple replicates of the high MADR line, whereas  Taar1   m1J   homozygotes were absent in the low MADR line. The homozygous  Taar1   m1J   genotype is causally linked to increased MA intake, reduced MA-induced conditioned taste aversion, and reduced MA-induced hypothermia across models. Genotype-phenotype correlations range from 0.68 to 0.96. This  Taar1  polymorphism exists in DBA/2J mice sourced directly from The Jackson Laboratory, but not DBA/2 mice sourced from Charles River (DBA/2NCrl), Envigo (formerly Harlan Sprague Dawley; DBA/2NHsd) or Taconic (DBA/2NTac). By genotyping archived samples from The Jackson Laboratory, we have determined that this mutation arose in 2001–2003. Our data strengthen the conclusion that the mutant  Taar1   m1J   allele, which codes for a non-functional receptor protein, increases risk for multiple MA-related traits, including MA intake, in homozygous  Taar1   m1J   individuals.

A Spontaneous Mutation in Taar1 Impacts Methamphetamine-Related Traits Exclusively in DBA/2 Mice from a Single Vendor