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Protein kinase mζ is necessary for cocaine-induced synaptic potentiation in the ventral tegmental area.
Biol Psychiatry. 2012 Apr 15; 71(8):706-13.BP

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+Show Affiliations

Department of Biological Sciences, National Sun Yat-Sen University, No 70 Lein-Hai Road,Kaohsiung, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22153887

Citation

Ho, Shih-Yin, et al. "Protein Kinase Mζ Is Necessary for Cocaine-induced Synaptic Potentiation in the Ventral Tegmental Area." Biological Psychiatry, vol. 71, no. 8, 2012, pp. 706-13.
Ho SY, Chen CH, Liu TH, et al. Protein kinase mζ is necessary for cocaine-induced synaptic potentiation in the ventral tegmental area. Biol Psychiatry. 2012;71(8):706-13.
Ho, S. Y., Chen, C. H., Liu, T. H., Chang, H. F., & Liou, J. C. (2012). Protein kinase mζ is necessary for cocaine-induced synaptic potentiation in the ventral tegmental area. Biological Psychiatry, 71(8), 706-13. https://doi.org/10.1016/j.biopsych.2011.10.031
Ho SY, et al. Protein Kinase Mζ Is Necessary for Cocaine-induced Synaptic Potentiation in the Ventral Tegmental Area. Biol Psychiatry. 2012 Apr 15;71(8):706-13. PubMed PMID: 22153887.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein kinase mζ is necessary for cocaine-induced synaptic potentiation in the ventral tegmental area. AU - Ho,Shih-Yin, AU - Chen,Chih-Hao, AU - Liu,Tsung-Han, AU - Chang,Hsiao-Fu, AU - Liou,Jau-Cheng, Y1 - 2011/12/09/ PY - 2011/06/22/received PY - 2011/10/20/revised PY - 2011/10/20/accepted PY - 2011/12/14/entrez PY - 2011/12/14/pubmed PY - 2012/8/17/medline SP - 706 EP - 13 JF - Biological psychiatry JO - Biol. Psychiatry VL - 71 IS - 8 N2 - 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. SN - 1873-2402 UR - https://www.unboundmedicine.com/medline/citation/22153887/Protein_kinase_mζ_is_necessary_for_cocaine_induced_synaptic_potentiation_in_the_ventral_tegmental_area_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(11)01045-6 DB - PRIME DP - Unbound Medicine ER -