Insular cortex dopamine 1 and 2 receptors in methamphetamine conditioned place preference and aversion: Age and sex differences

Rodent studies have proposed that adolescent susceptibility to substance use is at least partly due to adolescents experiencing reduced aversive effects of drugs compared to adults. We thus investigated methamphetamine (meth) conditioned place preference/aversion (CPP/CPA) in adolescent and adult mice in both sexes using a high dose of meth (3 mg/kg) or saline as controls. Mice tagged with green-fluorescent protein (GFP) at Drd1a or Drd2 were used so that dopamine receptor 1 (D1) and 2 (D2) expression within the insular cortex (insula) could be quantified. There are sex differences in how the density of D1+ and D2+ cells in the insula changes across adolescence that may be related to drug-seeking behaviors. Immunohistochemistry followed by stereology were used to quantify the density of cells with c-Fos and/or GFP in the insula. Unexpectedly, mice showed huge variability in behaviors including CPA, CPP, or no preference or aversion. Females were less likely to show CPP compared to males, but no age differences in behavior were observed. Conditioning with meth increased the number of D2 + cells co-labelled with c-Fos in adults but not in adolescents. D1:D2 ratio also sex- and age-dependently changed due to meth compared to saline. These findings suggest that reduced aversion to meth is unlikely an explanation for adolescent vulnerability to meth use. Sex- and age-specific expressions of insula D1 and D2 are changed by meth injections, which has implications for subsequent meth use.