Appearance of Extrapyramidal Symptoms: Interaction between Neuroleptics and Other CNS Active Drugs

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Abstract
Neuroleptics were able to induce motor incoordination when administered to rats in large amounts. It has been observed that this effect could be antagonized by some CNS active drugs endowed with dopaminergic stimulants, anticholinergic and antihistaminic properties (such as amphetamine, apomorphine, atropine and diphenhydramine), only when evoked by neuroleptics (haloperidol, metoclopramide and LR 511) causing muscle rigidity. Other antihistaminics blocking H i receptors (chlorpheniramine, chlorcyclizine, cyclizine and promethazine), but not those blocking H2 receptors (cimetidine), were also effective at least on haloperidol-induced incoordination. On the other hand, specific central antiserotoninergic drugs (metergoline and methysergide) and a peripheral anticholinergic agent (isopropamide) did not antagonize but in some cases potentiated haloperidol and LR 511. Chlorpromazine, clozapine and diazepam (a minor tranquilizer), causing motor incoordination only at doses which strongly relaxed the skeletal muscles, were generally not influenced, or at the most slightly potentiated, by any of the above-mentioned drugs. The incoordination induced by pilocarpine (a direct stimulator of the cholinergic receptors of the extrapyramidal system) was selectively inhibited by drugs possessing antimuscarinic properties (such as atropine and cyproheptadine). Thus, the present results indicate that along with the dopaminergic and cholinergic systems, the histaminergic system also plays an important role in modulating the extrapyramidal activity of hypertonic neuroleptics (revealed in rats by the locomotor incoordination) while, in disagreement with some data of the literature, the serotoninergic system should not have any significance.