PKMζ in the nucleus accumbens acts to dampen cocaine seeking

Abstract The constitutively active, atypical protein kinase C, protein kinase M-ζ (PKMζ), is exclusively expressed in the brain and its expression increases following exposure to drugs of abuse. However, the limitations of currently available tools have made it difficult to examine the role of PKMζ in cocaine addiction. The current study demonstrates that constitutive deletion of PKMζ potentiates cue-induced reinstatement of cocaine seeking and increases both food and cocaine taking, without affecting cue-driven food seeking in both male and female mice. Conditional deletion of PKMζ within the nucleus accumbens recapitulated the increase in cocaine taking and seeking seen in the constitutive knockout mice, but only in male animals. Site-specific knockdown of PKMζ in the nucleus accumbens had no effect on cocaine or natural reward behaviors in female mice. Taken together these results indicate that PKMζ may act to dampen addictive phenotypes. Furthermore, these results indicate that PKMζ is playing divergent roles in reward seeking in males and females.