Paternal epigenetic inheritance increases susceptibility to methamphetamine taking.

We previously demonstrated that male progeny of cocaine-experienced sires resisted cocaine, expressed as delayed acquisition of cocaine self-administration. Here, we sought to determine whether this phenotype extended to another psychostimulant, methamphetamine (meth). Sires self-administered meth or cocaine or received yoked-saline infusions for 60 days, after which they were mated to naïve females. Some behaviors previously altered in cocaine-sired male rats, including object memory and anxiety-like behavior, were not influenced by paternal meth taking. In contrast to cocaine resistance in cocaine-sired male rats, meth-sired male offspring demonstrated increased susceptibility to meth taking, with no effect in females. Single nuclei RNA- and ATAC-sequencing of the nucleus accumbens was used to identify molecular drivers of phenotypes in cocaine- and meth-sired offspring. Sequencing results revealed unique profiles of gene expression and open chromatin in offspring nucleus accumbens. Differential gene expression in cocaine-resistant, cocaine-sired offspring and meth-susceptible, meth-sired offspring illuminates potential novel treatment targets for psychostimulant use disorders.