PKMζ in the prefrontal cortex alters cocaine cue-induced reinstatement in a sex-specific manner

Cocaine alters glutamate in the prefrontal cortex (PFC), which is a region critical for mediating relapse behaviors. Long-lasting changes in glutamate transmission indicate a role for cocaine-induced synaptic plasticity in the reward circuit. Protein kinase M-ζ (PKMζ), a constitutively active isoform of protein kinase C (PKC), plays a critical role in AMPA receptor (AMPAR) trafficking, including that which occurs after drug exposure. There is evidence for a role of PKMζ in drug reward as constitutive deletion of PKMζ potentiates cocaine self-administration. As the PFC plays a role in drug reward and PKMζ deletion disrupts plasticity the in PFC, we sought to investigate the role of PKMζ within this brain region. Using an inducible genetic deletion model to selectively knockdown PKMζ in the PFC of male and female mice we sought to investigate the role of PFC PKMζ in cocaine taking and seeking behaviors. We did not see an effect of PFC PKMζ knockout on cocaine taking during fixed-ratio self-administration nor am effect on motivation for cocaine on a progressive ratio schedule of reinforcement. However, we found that female, but not male mice, with PFC PKMζ knockout have blunted cue-induced cocaine seeking. In combination previous studies, PKMζ is not playing a uniform role in cocaine taking, seeking, or motivation across region. Instead, it is likely that PKMζ may have additional roles in altering glutamatergic transmission that have yet to be delineated. Sex differences in cue-induced reinstatement may be due to these sex and regional specific differences in PKMζ mechanism.