Profound reduction in sensitivity to the aversive effects of methamphetamine in mice bred for high methamphetamine intake

Abstract

Reduced sensitivity to aversive effects of methamphetamine (MA) may increase risk for MA abuse. Studies in two replicate sets of mouse lines that were selectively bred for high and low levels of MA intake support this view. Current studies examined the extent of insensitivity to aversive MA effects of mice bred for high levels of MA drinking. Conditioning procedures in which drugs are delivered shortly after cue exposure have been used to detect aversive drug effects and, in some cases, are more sensitive to such effects. Aversive effects induced by MA injected immediately after exposure to cues from two different sensory modalities were examined. In addition, effects of higher MA doses than those used previously were examined. MA-associated place conditioning utilized tactile cues, whereas MA-induced taste conditioning utilized a novel tastant. Second replicate, MA high drinking (MAHDR-2) and low drinking (MALDR-2) mice were treated with doses of MA up to 4 mg/kg. MAHDR-2 mice were insensitive to aversive effects of MA, except after place conditioning with the 4 mg/kg dose; MALDR-2 mice exhibited sensitivity to aversive effects of MA at doses as low as 1 mg/kg. These studies show that the expression of aversion is dependent upon procedure and MA dose, and that MAHDR-2 mice have markedly reduced sensitivity to the aversive effects of MA. The current and previous results support a strong genetic relationship between level of MA intake and level of sensitivity to aversive effects of MA, a factor that could impact risk for MA use in humans. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Figure 1

B6D2F2 mice display conditioned place aversion (CPA) to a wide range of methamphetamine (MA) doses. (A and B) Time in sec/min on the grid floor during a 30-min test for mice previously conditioned with MA on the grid (G+) or on the hole (G−) floor (n = 7–8 per group and dose). (C and D) Percent (%) time spent on the MA-paired floor by the same animals for the same 30-min test as for the data shown in A and B. Data are collapsed on conditioning group (G+ vs G−) and sex, due to the absence of significant effects of these factors; n = 14–16 per dose. Shown are means ± SEM. ***p<.001 for the main effect of conditioning group.

Figure 2

MALDR-2 mice display MA-induced conditioned place aversion (CPA) at a lower MA dose than MAHDR-2 mice. (A and B) Time in sec/min on the grid floor during a 30-min test for mice previously conditioned with MA on the grid (G+) or on the hole (G−) floor (n = 10–13 per line, group and dose). (C) Percent (%) time on the MA-paired floor by the same animals for the same 30-min test as for the data shown in A and B. Data are collapsed on conditioning group (G+ vs G−) and sex, due to the absence of significant effects of these factors; n = 20–23 per line and dose. Shown are means ± SEM. ***p<.001 for the comparison of G+ and G− at the specific MA dose. **p<.005 for the line comparison at the specific MA dose. MAHDR-2, MA high drinking replicate 2; MALDR-2, MA low drinking replicate 2.

Figure 3

MAHDR-2 mice are insensitive to MA-induced conditioned taste aversion (CTA) at doses that produce profound CTA in MALDR-2 mice. MALDR-2 mice (n = 12 per sex and dose) received injections of saline, 1 or 2 mg/kg MA, whereas MAHDR-2 mice (n = 12 per sex and dose) received injections of saline, 2 or 4 mg/kg MA, immediately following consumption of 0.2 M NaCl on days 7, 9, 11 and 13. (A) Consumption of 0.2 M NaCl in MAHDR-2 mice. (B) Consumption of 0.2 M NaCl in MALDR-2 mice. Shown are means ± SEM for data collapsed on sex because there was no significant effect of this factor. *p<.01 for indicated day vs day 7. MAHDR-2, MA high drinking replicate 2; MALDR-2, MA low drinking replicate 2.

Figure 4

Plasma MA levels in male MAHDR-2 and MALDR-2 mice at several time points following ip administration of 2 mg/kg MA. N=4–5 mice per line and time point. *** p<.001 for the line comparison at the 15-min time point.