PKMζ alters oxycodone-taking in a dose- and sex-dependent manner

Opioid use disorder involves disruptions to glutamate homeostasis and dendritic spine density in the reward system. PKM is an atypical isoform of protein kinase C that is expressed exclusively in neurons and plays a role in postsynaptic glutamate signaling and dendritic spine maturation. As opioid use leads to alterations in glutamate transmission and dendritic spine density, we hypothesized that PKM deletion would alter opioid-taking behaviors. The current study examined two doses of oxycodone self-administration in male and female mice with constitutive deletion of PKM compared to wildtype controls. At a dose of 0.25 mg/kg/infusion, PKM deletion significantly potentiated oxycodone self-administration in both male and female mice. However, increases in motivation for oxycodone, as indicated by increased breakpoint on a progressive ratio schedule, were only seen in male PKM knockout mice and not females. When we examined a lower dose of oxycodone, 0.125 mg/kg/infusion, PKM knockout led to increases in oxycodone self-administration only in female mice. Additionally, female PKM knockout mice exhibited higher breakpoints on a progressive ratio schedule at this dose compared to all other groups. In addition to the self-administration studies, we also examined locomotor sensitization in response to experimenter administered oxycodone. PKM KO decreased oxycodone induced locomotion in males and potentiated oxycodone sensitization in females. Together, these results suggest that PKM acts to dampen oxycodone taking in both sexes, but females may be more sensitive to its effects.