CALCIUM-MEDIATED 2ND-MESSENGERS MODULATE THE EXPRESSION OF BEHAVIORALSENSITIZATION TO COCAINE

To assess the influence of calcium channel antagonists on the expressi on of behavioral sensitization to cocaine, the L-type calcium channel antagonist diltiazem or the N-type calcium channel antagonist omega-co notoxin GVIA was microinjected into the medial nucleus accumbens befor e a systemic cocaine challenge injection among rats that were previous ly treated with daily systemic saline or cocaine injections. The resul ts indicated that both of these drugs attenuated the expression of beh avioral sensitization to cocaine. Among saline-pretreated rats, diltia zem did not influence the behavioral response to an acute injection of cocaine, whereas w-conotoxin significantly impaired acute cocaine-ind uced behavioral hyperactivity. A second series of experiments assessed the influence of protein kinases on the expression of behavioral sens itization to cocaine. Inhibitors of calcium/calmodulin-dependent prote in kinase II (KN-93, N-[2-[[[3-(4'-chlorophenyl)-2-propenyl]methylamin o ]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxy- benzenesulfonamide ph osphate), protein kinase A (H-89, mocinnamyl)amino)ethyl]-5-isoquinoli nesulfonamide) or calcium-dependent protein kinase C (bisindolymale-im ide 1, 2-[1 ropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) were mi croinjected into the medial nucleus accumbens before a challenge injec tion of cocaine among rats repeatedly administered either saline or co caine. None of the kinase inhibitors influenced the behavioral respons e induced by cocaine in saline-pretreated rats. Among cocaine-sensitiz ed animals, the microinjection of KN-93 or bisindolymaleimide I blocke d the expression of behavioral sensitization to cocaine, whereas H-89 had no effect. Taken together, these results indicate that neuronal ca lcium, acting via calcium-dependent kinases, promotes the expression o f behavioral sensitization to cocaine.