Mechanisms of dyskinesia induction by 1-(3,4-dihydroxyphenyl) piperazine in the rat

Abstract

The unilateral intrastriatal (caudate-putamen) administration of 1-(3,4-dihydroxyphenyl) piperazine in the rat induced abnormal involuntary movements involving myoclonic jerks of the contralateral forelimb, facial grimacing and intense twisting of the head and neck region. At larger doses, and after bilateral injection, both ipsilateral and contralateral muscle groups were affected. Identical effects were observed after injections into the globus pallidus (after larger doses and delayed onset), tuberculum olfactorium (delayed onset), nucleus accumbens septi, hippocampus and cerebral cortex, but typical abnormal involuntary movements were not observed after injections into the thalamus, midbrain reticular formation and substantia nigra. From a large number of phenylpiperazine derivatives tested, only 1-(3-hydroxyphenyl) piperazine induced abnormal involuntary movements but the effect was less than that of 1-(3,4-dihydroxyphenyl) piperazine. However, intrastriatal picrotoxin, (+)-tubocurarine and carbachol induced effects identical to those of 1-(3,4-dihydroxyphenyl) piperazine. The effects of 1-(3,4-dihydroxyphenyl) piperazine were not inhibited by peripherally administered haloperidol, fluphenazine, clothiapine, oxiperomide, spiroxatrine, morphine, aceperone, piperoxan, propranolol (except at very large doses), practolol, atropine, orphenadrine, mecamylamine or cyproheptadine. Similarly, larger doses of the anticonvulsants sodium phenobarbitone, phenytoin and diazepam failed to inhibit the 1-(3,4-dihydroxyphenyl) piperazine abnormal involuntary movements, except at an anaesthetic dose of phenobarbitone. Unilateral intrastriatal injections of atropine, propranolol, piperoxan, fluphenazine, dopamine or procaine also failed to modify the action of 1-(3,4-dihydroxyphenyl) piperazine. However, complete inhibition of the abnormal involuntary movements was achieved by the intrastriatal administration of γ-aminobutyric acid and sodium valproate. Sodium valproate was also effective by peripheral administration. In addition, unilateral intrastriatal serotonin abolished the 1-(3,4-dihydroxyphenyl) piperazine effects. Results indicate modulatory effects of γ-aminobutyric acid and serotonin on the activity of the dopamine-containing striatum in the control of motor function.