Abstract
To assess the influence of calcium channel antagonists on the expression of behavioral sensitization to cocaine, the L-type calcium channel antagonist diltiazem or the N-type calcium channel antagonist ω-conotoxin GVIA was microinjected into the medial nucleus accumbens before a systemic cocaine challenge injection among rats that were previously treated with daily systemic saline or cocaine injections. The results indicated that both of these drugs attenuated the expression of behavioral sensitization to cocaine. Among saline-pretreated rats, diltiazem did not influence the behavioral response to an acute injection of cocaine, whereas ω-conotoxin significantly impaired acute cocaine-induced behavioral hyperactivity. A second series of experiments assessed the influence of protein kinases on the expression of behavioral sensitization to cocaine. Inhibitors of calcium/calmodulin-dependent protein kinase II (KN-93, N-[2-[[[3-(4′-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4′-methoxy-benzenesulfonamide phosphate), protein kinase A (H-89, N-[2((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide) or calcium-dependent protein kinase C (bisindolymaleimide I, 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) were microinjected into the medial nucleus accumbens before a challenge injection of cocaine among rats repeatedly administered either saline or cocaine. None of the kinase inhibitors influenced the behavioral response induced by cocaine in saline-pretreated rats. Among cocaine-sensitized animals, the microinjection of KN-93 or bisindolymaleimide I blocked the expression of behavioral sensitization to cocaine, whereas H-89 had no effect. Taken together, these results indicate that neuronal calcium, acting viacalcium-dependent kinases, promotes the expression of behavioral sensitization to cocaine.
Footnotes
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Send reprint requests to: Dr. Chris Pierce, Department of Pharmacology, R-612, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118-2394. E-mail:rcpierce{at}acs.bu.edu
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↵1 This work was supported by the Washington State Alcohol and Drug Abuse Program, United States Public Health Service Grants MH40817 and DA03906 and Research Career Development Award DA00158 (P.W.K.), as well as a National Alliance for Research on Schizophrenia and Depression Young Investigator Award and USPHS grant DA11168 (R.C.P.).
- Abbreviations:
- ANOVA
- analysis of variance
- CaM-KII
- calcium/calmodulin-dependent protein kinase II
- PKA
- protein kinase A
- PKC
- protein kinase C
- Received January 22, 1998.
- Accepted April 15, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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