Chronic haloperidol treatment increased calcium-dependent phosphorylation in rat striatum.
In previous studies, we observed that when rats were chronically treated wih haloperidol, there was a significant increase of calmodulin activity in their striatal membranes. Calmodulin is known to modulate calcium-dependent protein phosphorylation in neural membranes. In the present study, we found that the total 32P-incorporation in the striatal proteins from chronic haloperidol-treated rats was significantly increased in comparison to saline-treated rats. A majority of the phosphorylation was attributed to the calcium-mediated activity, since it could be blocked by a calcium chelating agent (EGTA). By using EGTA to inhibit phosphorylation, the results indicated that the haloperidol-treated rats had approximately 3.5-fold greater Ca++-dependent protein kinase activity than the saline-treated rats. Exogenous calcium alone was insufficient to stimulate phosphorylation in the haloperidol-treated rats to the same magnitude as in the saline-treated rats. Calmodulin may be required. 32P-incorporation of two striatal proteins at molecular weight 40 and 52 kilodaltons were markedly stimulated by calcium. Cyclic AMP-mediated phosphorylation seemed to take only a small part in the alteration of total phosphorylation. Therefore, the increase of calmodulin activity and calcium-dependent phosphorylation appears to play a major role in the drug-induced dopamine receptor supersensitivity in rat striatum.
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D002135:Calcium-Binding Proteins; D002147:Calmodulin; D000242:Cyclic AMP; D011494:Protein Kinases; D006220:Haloperidol; D002118:Calcium