Effects of dopamine agonists, catecholamine depletors, and cholinergic and GABAergic drugs on acute dyskinesias in squirrel monkeys.
It has been suggested that the neuroleptic-induced acute dyskinetic syndrome in monkeys may be a useful model of extrapyramidal dysfunction. Various drugs that have well-characterized effects on clinical extrapyramidal syndromes and on catecholaminergic, cholinergic, or GABAergic neurotransmission were assessed in dyskinesia-susceptible squirrel monkeys. Catecholamine depletors (alpha-methyl-p-tyrosine, tetrabenazine) induced the syndrome, as do dopamine (DA) receptor antagonists, and d-amphetamine reversed the effects of tetrabenazine. The haloperidol-induced syndrome was reversed by the indirectly acting DA agonists amantadine and L-dopa. Neither of the DA autoreceptor agonist TL-99 or 3-PPP elicited this syndrome, suggesting that these agents lack extrapyramidal involvement. Anticholinergics reversed haloperidol-induced dyskinesias and the cholinomimetic arecoline was capable of inducing dyskinesias. When coadministered repeatedly with haloperidol, benztropine suppressed the emergence of susceptibility to neuroleptic-induced dyskinesias. These results confirm that the acute dyskinetic syndrome in the monkey is characterized by DA deficiency and acetylcholine excess. Diazepam and baclofen, which have been reported to have some clinical benefit in tardive dyskinesia, suppressed haloperidol-induced acute dyskinesias without causing gross motor depression. Pharmacological manipulation of GABAergic pathways from striatum may constitute a fruitful approach to the treatment of dyskinetic motor disorders.
D000208:Acute Disease; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002395:Catecholamines / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000517:prevention & control; D006220:Haloperidol / Q000037:antagonists & inhibitors; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011954:Receptors, Dopamine / Q000187:drug effects*; D011963:Receptors, GABA-A; D012453:Saimiri; D019805:alpha-Methyltyrosine; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D002395:Catecholamines; D008781:Methyltyrosines; D010277:Parasympathomimetics; D011956:Receptors, Cell Surface; D011954:Receptors, Dopamine; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D019805:alpha-Methyltyrosine; D006220:Haloperidol