Persistent Reversal of Enhanced Amphetamine Intake by Transient CaMKII Inhibition
| Autor: | Jessica A. Loweth, Georgia Wilke, James J. Cortright, Rachael L. Neve, Paul Vezina, K. U. Bayer, Dongdong Li, Okunola Jeyifous |
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| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Amphetamine-Related Disorders Immunoblotting Nucleus accumbens Pharmacology Nucleus Accumbens Article Rats Sprague-Dawley Ca2+/calmodulin-dependent protein kinase Internal medicine medicine Animals Rats Long-Evans Amphetamine Sensitization Chemistry General Neuroscience Immunohistochemistry Rats Stimulant medicine.anatomical_structure Endocrinology nervous system Phosphorylation Central Nervous System Stimulants Signal transduction Calcium-Calmodulin-Dependent Protein Kinase Type 2 Self-administration Signal Transduction medicine.drug |
| Zdroj: | The Journal of Neuroscience. 33:1411-1416 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.4386-13.2013 |
| Popis: | Amphetamine exposure transiently increases Ca2+/calmodulin-dependent protein kinase II (CaMKII) α expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction. |
| Databáze: | OpenAIRE |
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