title: Protein kinase mζ is necessary for cocaine-induced synaptic potentiation in the ventral tegmental area.
abstract: 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 Mζ (PKMζ) 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 PKMζ on the behavioral responses by cocaine conditioned place preference.
  
  
  RESULTS
  Chelerythrine, an inhibitor of PKMζ, reversed the cocaine-induced facilitation of spontaneous synaptic transmission in the VTA. PKMζ inhibition by chelerythrine or myristoylated ζ inhibitory peptide significantly attenuated the cocaine exposure-induced enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio. Myristoylated ζ 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 PKMζ level. Furthermore, intracranial infusion of myristoylated ζ inhibitory peptide in the VTA disrupted cocaine conditioned place preference.
  
  
  CONCLUSIONS
  Our results suggest that persistent activity of PKMζ is a requisite for cocaine-induced enhancement of synaptic plasticity in the VTA and cocaine conditioned place preference.
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, No 70 Lein-Hai Road,Kaohsiung, Taiwan.
authors.forename: Shih-Yin
authors.initials: SY
authors.lastname: Ho
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chen
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Liu
authors.forename: Hsiao-Fu
authors.initials: HF
authors.lastname: Chang
authors.forename: Jau-Cheng
authors.initials: JC
authors.lastname: Liou
mesh_terms: D000818:Animals; D053119:Benzophenanthridines / Q000378:metabolism; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: D053119:Benzophenanthridines; D016194:Receptors, N-Methyl-D-Aspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C016299:chelerythrine; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat; D003042:Cocaine