Increased sensitivity of adenylate cyclase activity in the striatum of the rat to calmodulin and GppNHp after chronic treatment with haloperidol

G. J. Treisman, N. Muirhead, M. E. Gnegy

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Abstract

Chronic treatment of rats with haloperidol causes behavioral supersensitivity to dopaminergic agonists and an increase in the sensitivity of adenylate cyclase activity in the striatum to stimulation by dopamine. In this study the authors examined whether chronic treatment with haloperidol could elicit a change in sensitivity of adenylate cyclase in the striatum of the rat for guanyl nucleotides and the endogenous Ca2+-binding protein, calmodulin. These agents increase the activation of adenylate cyclase activity by dopamine but act beyond the level of the dopamine receptor. Male, Sprague-Dawley rats were injected subcutaneously with either 0.6 mg/kg haloperidol or vehicle for 14 days. Four days after the last injection, the animals were sacrificed and the activity of adenylate cyclase was measured in a EGTA-washed particulate preparation of the striatum. There was an increase in the activation of adenylate cyclase activity by calmodulin and GppNHp but not by guanosine triphosphate (GTP) in particulate fractions of the striatum from rats treated with haloperidol as compared to controls. The sensitivity of adenylate cyclase to calmodulin was increased 5-fold in particulate fractions from rats treated with haloperidol as opposed to vehicle-treated rats. The lack of change in activation by GTP was not due to an altered activity of GTPase in rats treated with haloperidol. In animals treated for 14 days but not withdrawn from haloperidol there was no statistically significant increase in the sensitivity of adenylate cyclase to calmodulin. There was no change in activation of the enzyme by GppNHp or GTP as compared to control. The activation of adenylate cyclase by calmodulin was not affected when haloperidol was added in vitro to the assay or after the acute injection of rats with haloperidol. These results demonstrate that the development of dopaminergic supersensitivity after withdrawal from chronic blockade of dopamine receptors resulted in increased sensitivity of post-receptor coupling mechanisms, as well as in changes in the receptor-mediated activity. In previous studies, increases in DA-stimulated adenylate cyclase activity were found with this treatment regimen. In this study it was shown that although basal activity was not changed, there was a selective increase in the sensitivity of adenylate cyclase to stimulation by calmodulin and GppNHp after chronic receptor blockade. These findings support previous observations suggesting a regulatory role for calmodulin in dopaminestimulated adenylate cyclase activity.

Original languageEnglish (US)
Pages (from-to)587-595
Number of pages9
JournalNeuropharmacology
Volume25
Issue number6
DOIs
StatePublished - Jun 1986

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Keywords

  • adenylate cyclase
  • calmodulin
  • dopamine
  • haloperidol
  • supersensitivity

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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