Participation of an endogenous Ca++-blinding protein activator in the development of drug-induced supersensitivity of striatal dopamine receptors
Gnegy, M.; Uzunov, P.; Costa, E.
Journal of Pharmacology and Experimental Therapeutics 202(3): 558-564
1977
ISSN/ISBN: 0022-3565 PMID: 19618 Document Number: 120123
In order to examine the molecular mechanism of supersensitivity of striatal dopamine (DA) receptors, which were developed after chronic treatment with some neuroleptics, the amount of the Ca2+-dependent protein activator of adenylate cyclase and phosphodiesterase was measured in the striatum. The supersensitivity of the striatal dopaminergic receptors, measured both as increased behavioral response to apomorphine and as increased DA-stimulated adenylate cyclase activity, was studied after chronic injection with haloperidol, clozapine and (+)- and (-)-butaclamol. The membrane fraction of rat striata treated with haloperidol or (+)-butachlamol, neuroleptics which produce supersensitivity of striatal DA receptors, had greater activator amounts and greater DA-stimulated adenylate cyclase activity than the saline-treated control rats. The activator content and DA-stimulated adenylate cyclase activity of the rat striate treated with clozapine, an antipsychotic which fails to induce supersensitivity and (-)-butaclamol, which is inactive as a neuroleptic, were the same as in the saline-treated animals. Since this Ca2+-binding protein is known to participate in the adenylate cyclase activation the greater activator amounts contained in the striata membrane fraction displaying DA supersensitivity could apparently be a factor operative in this supersensitivity caused by treatment with neuroleptics.