SEX DIFFERENCES IN THE ROLE OF PKMζ IN DRUG SELF-ADMINISTRATION AND PREFRONTAL CORTEX SYNAPTIC PLASTICITY
Neuroadaptations associated with addiction are hypothesized to involve the same glutamatergic cellular mechanisms that underlie learning and memory. Further, there are clear sex differences in both rates of diagnosis and symptom severity in substance use disorder which may result from sexually dimorphic pathophysiology involving glutamate. However, little is known about the contribution of role of proteins involved in synaptic plasticity in reward related circuitry. The goal of these experiments was to determine the role of protein kinase M zeta (PKMζ), a protein involved in the trafficking of AMPA receptors (AMPARs), in drug taking behaviors and synaptic plasticity. PKMζ belongs to the protein kinase C family and is exclusively in the central nervous system. PKMζ is persistently active, making it an interesting target for persistent changes in the brain, such as memory storage. Although the exact role PKMζ synaptic plasticity has been the source of controversy, there is a known role for PKMζ in reward. Mice genetically lacking PKMζ exhibit heightened addictive phenotypes for both ethanol and cocaine. We extended these findings to the opioid drug class and found that PKMζ works to dampen reward in male and female mice. We next examined the role for PKMζ in long term synaptic plasticity in the medial prefrontal cortex, a region critical for the expression of addictive phenotypes. We found that PKMζ is necessary for both long term depression and long-term potentiation in the mPFC. Finally, we investigated the role of PKMζ specifically in the PFC on cocaine taking behaviors. We found that PFC PKMζ plays a sex-specific role in cocaine cue-induced reinstatement. Taken together these findings suggest PKMζ has sex- and region-specific role in synaptic plasticity and reward related behaviors and gaining more insight into these mechanisms may provide novel routes for the treatments of substance use disorder.
Neurosciences, Cocaine, Oxycodone, PKMζ, Prefrontal cortex, Sex, Synaptic plasticity, Psychology
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