Repeated amphetamine administration alters the interaction between D1-stimulated adenylyl cyclase activity and calmodulin in rat striatum

Abstract

The effect of repeated intermittent treatment with amphetamine on the responses of rat striatal adenylyl cyclase to the D1 dopamine receptor agonist, SKF38393 [(+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride], and potentiative interactions with the endogenous Ca(++)-binding protein, calmodulin, were investigated. Female Sprague-Dawley rats were treated with saline or an escalating dose regimen of amphetamine for 4 weeks and withdrawn from treatment for either 2 or 4 weeks. Thirty minutes before sacrifice, rats in both groups were given a challenge dose of either saline or 1.0 mg/kg of amphetamine. In striatal membranes from rats chronically treated with saline and withdrawn 4 weeks, calmodulin increased SKF38393-stimulated adenylyl cyclase activity by 195% over that seen in the presence of GTP alone. In contrast, this pronounced potentiative interaction was absent in rats chronically treated with amphetamine. The lack of potentiation by calmodulin was independent of length of withdrawal from the drug or amphetamine challenge. Although the repeated amphetamine treatment abolished the potentiative response to calmodulin, this treatment significantly increased the calmodulin content in the striatal cytosol by 40%. Heightened responsiveness of several dopamine-related neurochemical activities was evident after an amphetamine challenge to rats that had been treated repeatedly with amphetamine. A challenge dose of 1 mg/kg of amphetamine decreased SKF38393-stimulated adenylyl cyclase activity in amphetamine-treated but not saline-treated rats. The degree of desensitization induced by amphetamine challenge was heightened with increased length of withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)