Differential genetic risk for methamphetamine intake confers differential sensitivity to the temperature-altering effects of other addictive drugs

Abstract

Mice selectively bred for high methamphetamine (MA) drinking (MAHDR), compared with mice bred for low MA drinking (MALDR), exhibit greater sensitivity to MA reward and insensitivity to aversive and hypothermic effects of MA. Previous work identified the trace amine-associated receptor 1 gene (Taar1) as a quantitative trait gene for MA intake that also impacts thermal response to MA. All MAHDR mice are homozygous for the mutant Taar1 ^m1J allele, whereas all MALDR mice possess at least one copy of the reference Taar1 ⁺ allele. To determine if their differential sensitivity to MA-induced hypothermia extends to drugs of similar and different classes, we examined sensitivity to the hypothermic effect of the stimulant cocaine, the amphetamine-like substance 3,4-methylenedioxymethamphetamine (MDMA), and the opioid morphine in these lines. The lines did not differ in thermal response to cocaine, only MALDR mice exhibited a hypothermic response to MDMA, and MAHDR mice were more sensitive to the hypothermic effect of morphine than MALDR mice. We speculated that the μ-opioid receptor gene (Oprm1) impacts morphine response, and genotyped the mice tested for morphine-induced hypothermia. We report genetic linkage between Taar1 and Oprm1; MAHDR mice more often inherit the Oprm1 ^D2 allele and MALDR mice more often inherit the Oprm1 ^B6 allele. Data from a family of recombinant inbred mouse strains support the influence of Oprm1 genotype, but not Taar1 genotype, on thermal response to morphine. These results nominate Oprm1 as a genetic risk factor for morphine-induced hypothermia, and provide additional evidence for a connection between drug preference and drug thermal response.

Keywords: addiction; methamphetamine; opioids; thermal regulation; trace amine-associated receptor 1; μ-opioid receptor.

Figure 1.

Mice bred for high and low methamphetamine (MA) intake exhibit similar sensitivity to the hypothermic effects of cocaine. There were no significant effects of sex involving line or cocaine dose, therefore the data are presented for the sexes combined. Shown are the effects of (a) saline, (b) 15 mg/kg cocaine, and (c) 30 mg/kg cocaine on core body temperature in MAHDR and MALDR mice across time in minutes (min). Data are means ± SEM. ++p < 0.01, and +++p < 0.001 for temperature change from T0 at the indicated time point for the main effect of time. MAHDR: methamphetamine high drinking; MALDR: methamphetamine low drinking

Figure 2.

Mice bred for low methamphetamine (MA) intake are more sensitive to hypothermic effects of MDMA on core body temperature than mice bred for high methamphetamine intake. There were no significant effects of sex involving line or dose, so the data are presented for the sexes combined. Shown are the effects of (a) saline, (b) 2.5 mg/kg MDMA, and (c) 5 mg/kg MDMA on body temperature in MAHDR and MALDR mice across time in minutes (min). Data are means ± SEM. +p < 0.05 and +++p < 0.001 for temperature change from T0 at the indicated time point for (a) the main effect of time, (b) the MAHDR line, and (c) the MALDR line; *p < 0.05, **p < 0.01, and ***p < 0.001 for the difference between the lines at the indicated time point. MAHDR: methamphetamine high drinking; MALDR: methamphetamine low drinking; MDMA: 3,4-methylenedioxymethamphetamine

Figure 3.

Mice bred for high methamphetamine (MA) intake are more sensitive to the hypothermic effects of morphine than mice bred for low methamphetamine intake. Because sex did not play a role in line-dependent responses to morphine, the data are presented for the sexes combined. Shown are the effects of (a) saline, (b) 15 mg/kg morphine, and (C) 30 mg/kg morphine on core body temperature in MAHDR and MALDR mice across time in minutes (min). Data are means ± SEM. +p < 0.05, ++p < 0.01, and +++p < 0.001 for temperature change from T0 at the indicated time point for (a) the main effect of time; (b and c) the MAHDR or MALDR line; *p < 0.05, **p < 0.01, and ***p < 0.001 for the difference between the lines at the indicated time point. MAHDR: methamphetamine high drinking; MALDR: methamphetamine low drinking

Figure 4.

(a) Oprm1 and (b) Taar1 genotype frequencies for methamphetamine high and low drinking mice tested in the study of morphine thermal effects. +: reference Taar1 allele; B6: C57BL/6J; D2: DBA/2J; m1J: mutant Taar1 allele found only in D2 mice; MAHDR: methamphetamine high drinking; MALDR: methamphetamine low drinking; Oprm1: mu-opioid receptor gene; Taar1: trace amine-associated receptor 1 gene

Figure 5.

Mice possessing the Oprm1^D2/D2 genotype are more sensitive to the hypothermic effects of morphine than Oprm1^B6/B6 mice. There were no interactions of sex and morphine dose, therefore data are presented for the sexes combined. Shown are the effects of saline, 15 mg/kg morphine, and 30 mg/kg morphine on core body temperature across time in minutes (min) for BXD RI mice with (a-c) Oprm1^B6/B6 and Orpm1^D2/D2 genotypes and (d-f) Taar1^+/+ and Taar1^m1J/m1J genotypes. +++p < 0.001 for temperature change from T0 at the indicated time point for the main effect of time (a,d-f) or for the Oprm1^B6/B6 or Oprm1^D2/D2 genotype (b,c); **p < 0.01, ***p < 0.001 for differences between genotypes at the indicated time point. +: reference Taar1 allele; B6: C57BL/6J; D2: DBA/2J; m1J: mutant Taar1 allele found only in D2 mice; Oprm1: mu-opioid receptor gene; Taar1: trace amine-associated receptor 1 gene