Protein Kinase Mζ Is Necessary for Cocaine-Induced Synaptic Potentiation in the Ventral Tegmental Area

Background: Much progress has been made in our understanding of brain regions and specific receptors that are involved in the action of cocaine addiction. Although long-term modifications of mesolimbic reward circuit following cocaine exposure are responsible for cocaine-addicted behaviors, the underlying molecular mechanism at the cellular level is still obscure. Here, we investigated the possible participation of protein kinase M zeta (PKM zeta) in synaptic potentiation following cocaine exposure. Methods: Spontaneous and evoked synaptic activity of glutamate synapse in saline- and cocaine-treated rats were examined by preparing acute brain slices and performing whole-cell voltage-clamp recordings from individual dopamine neurons in the ventral tegmental area (VTA). We also assessed the role of PKM zeta on the behavioral responses by cocaine conditioned place preference. Results: Chelerythrine, an inhibitor of PKM zeta, reversed the cocaine-induced facilitation of spontaneous synaptic transmission in the VTA. PKM zeta inhibition by chelerythrine or myristoylated zeta inhibitory peptide significantly attenuated the cocaine exposure-induced enhancement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio. Myristoylated zeta inhibitory peptide had no effect on spike timing-dependent long-term potentiation in rats previously injected with saline but remarkably restored spike timing-dependent long-term potentiation in VTA dopamine neurons in slices prepared from rats that received single or multiple cocaine exposure. Western blot analyses showed that both single and five consecutive cocaine injections induced a significant increase in PKM zeta level. Furthermore, intracranial infusion of myristoylated zeta inhibitory peptide in the VTA disrupted cocaine conditioned place preference. Conclusions: Our results suggest that persistent activity of PKM zeta is a requisite for cocaine-induced enhancement of synaptic plasticity in the VTA and cocaine conditioned place preference.