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 self-administration and relapse. The current study demonstrates that constitutive deletion of PKMζ potentiates cue-induced reinstatement of cocaine seeking and increases both food and cocaine self-administration, 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 taking or seeking in female mice. Additionally, neither male nor female mice exhibited any alterations in food self-administration or cue-induced reinstatement of food seeking following accumbal deletion of PKMζ. Taken together these results indicate that PKMζ may act to dampen cocaine taking and seeking. Furthermore, these results indicate that PKMζ is playing divergent roles in reward seeking in males and females.

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

“…In addition, the Prkcz gene, encoding the PKMζ (protein kinase Mζ) isoform of protein kinase C, has been linked to cocaine-mediated behaviors. Whereas initial studies posited a role for PKMζ in learning and memory, subsequent research has highlighted its potential in modulating cocaine-seeking behaviors as well, with a more pronounced effect observed in male mice ( 42 , 43 ).…”

Sex differences in pre- and post-synaptic glutamate signaling in the nucleus accumbens core

“…Behaviorally, constitutive PKMζ knockout reduces anxiety-like behavior in males but not females [ 58 ] and site-specific deletion of PKMζ in the NAc potentiates cocaine-taking exclusively in male mice [ 53 ]. Following exposure to cocaine and methamphetamine there are also sex-specific alterations to PKMζ expression [ 53 , 103 ]. Our data indicate PKMζ also plays a sex-specific role in LTD within the NAc.…”

“…This makes PKMζ an interesting target for studies on the synaptic plasticity underlying learning, memory, and motivated behavior. PKMζ is upregulated following performance of learning and memory tasks and cocaine experience [ 53 – 55 ]. Further, PKMζ is involved in depression- and anxiety-like behavior and drug-taking [ 53 , 56 – 59 ].…”

“…PKMζ is upregulated following performance of learning and memory tasks and cocaine experience [ 53 – 55 ]. Further, PKMζ is involved in depression- and anxiety-like behavior and drug-taking [ 53 , 56 – 59 ].…”

“…Interestingly, biological sex influences the role of PKMζ in these behaviors. While constitutive PKMζ knockout potentiates cocaine-taking in both sexes, site-specific knockout in the NAc potentiates cocaine-taking exclusively in males [ 53 ]. Constitutive PKMζ knockout also reduces anxiety-like behaviors in male, but not female, mice [ 58 ].…”