Role of calmodulin-dependent phosphorylation in chronic sulpiride-induced striatal dopamine receptor supersensitivity.
In the present study we investigated several pharmacological and biochemical parameters in striatal preparations of rats which were treated chronically with a selective D2 receptor antagonist, sulpiride. Chronic sulpiride treatment in rats (50 mg/kg s.c. for 20 days) potentiated stereotyped responses by apomorphine (0.1-2.5 mg/kg). In association with the dopaminergic behavior supersensitivity, we observed a significant increase in the number of specific [3H]spiperone binding sites (D2 receptors) in the striatum without affecting the ligand binding affinity constant. We further observed a marked increase in the sensitivity of the protein kinase to calcium (0.1-0.5 mM) and calmodulin (1 micrograms) in these rats. The D1 receptor functions which are represented by the basal and dopamine-stimulated adenylate cyclase and the cyclic AMP-dependent protein kinase activity were not changed after chronic sulpiride treatment. In vitro, pretreatment of striatal particulates with the Ca++-chelating agent ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (1.2 mM) to remove endogenous Ca++ and calmodulin or the addition of Ca++ and calmodulin to the striatal particulates did not affect the binding affinities of dopamine agonists and antagonists to the receptors. Therefore, the increased sensitivity of the calmodulin-dependent system seen in chronic sulpiride-treated rats correlates with the increased number of D2 receptors in striatal dopamine receptor supersensitivity.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002147:Calmodulin / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D008297:Male; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013134:Spiperone / Q000378:metabolism; D013469:Sulpiride / Q000494:pharmacology*
D002147:Calmodulin; D011954:Receptors, Dopamine; D013134:Spiperone; D013469:Sulpiride; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D001058:Apomorphine