EFFECT OF PIMOZIDE ON THE INCREASE OF MUSCARINIC RECEPTORS CAUSED BY MAZINDOL AND APOMORPHINE IN THE RAT CEREBRAL MOTOR CORTEX

The effects of pimozide, mazindol and apomorphine on muscarinic recept ors in homogenates of rat cerebral motor cortex were measured by bindi ng assays, using H-3-N-methylscopolamine (H-3-NMS) alone as ligand (fo r the measurement of M1- and M2-like receptors) or in the presence of carbachol or pirenzepine for determination of M1- and M2-like receptor s, respectively. Female Wistar rats (150 g) were treated daily for one week with pimozide, a dopaminergic antagonist (10 and 20 mg/kg, Po, b y gavage), or with apomorphine (1 mg/kg; ip). In another set of experi ments, animals were treated with pimozide and 30 min later with mazind ol (10 mg/kg, Po, by gavage) or apomorphine. The drugs were administer ed daily for one week. Controls received the same volume of saline. H- 3-NMS binding was increased from the control value of 418 +/- 17 to 54 8 +/- 42 fmol/mg protein by administration of mazindol (10 mg/kg) but binding was reduced to 360 +/- 11 fmol/mg protein upon administration of pimozide (20 mg/kg) plus mazindol (10 mg/kg). Similarly 10 mg/kg pi mozide reduced the increase in M1-like receptors caused by mazindol fr om 262 +/- 31 to 220 +/- 20 fmol/mg protein. Although 20 mg/kg pimozid e alone produced a decrease in M1- plus M2-like receptors (from 418 +/ - 17 to 348 +/- 22 fmol/mg protein), its action was preferentially on M2-like receptors, decreasing them from 148 +/- 10 to 111 +/- 15 fmol/ mg protein in the control and treated groups, respectively. At the hig her dose, 20 mg/kg pimozide also inhibited the H-3-NMS binding (M1- pl us M2-like receptors) in the presence of apomorphine (263 +/- 25 vs 41 8 +/- 17 fmol/mg protein. In contrast, apomorphine alone caused an inc rease (from 187 +/- 14 to 280 +/- 55 fmol/mg protein) and a decrease(f rom 148 +/- 10 to 101 +/- 9 fmol/mg protein) in M1- and M2-like recept ors, respectively, and the final action seems to be the result of the balance between these two opposite effects. The present results emphas ize the known interaction between cholinergic and dopaminergic systems in the cerebral motor cortex, and show that pimozide, besides blockin g the effect of mazindol on muscarinic cholinergic receptors, also alt ered H-3-NMS binding when administered in combination with apomorphine .