Effects of dopamine agonists, catecholamine depletors, and cholinergic and GABAergic drugs on acute dyskinesias in squirrel monkeys

Abstract

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.

The pharmacological characterisation of pilocarpine-induced purposeless chewing behaviour in the rat

“…This suggests some involvement of central cholinergic systems. Neuroleptic-induced acute dyst0nia in man and primates can also be controlled by administration of anficholinergic drugs (Meldrum et al 1977;Casey et al 1980;Porsolt and Jalfre 1981), and cholinergic agonists such as arecoline or physostigmine can exaggerate dystonic reactions initiated by neuroleptics in primates (Neale et al 1984;Casey et al 1980), again suggesting a key role for cholinergic systems.…”

Effects of Methamphetamine on Cortisone Concentration, NK Cell Activity and Mitogen Response of T-lymphocytes in Female Cynomolgus Monkeys

“…When MAP is administered, drowsiness and fatigue disappear, resulting in transient elevation of mental and physical activity tional behavior of AMP-administered rats as well as changes in metabolism, neurotransmitter, behavior, diet/ water intake and endocrinology when AMP or MAP is administered. Although there are some studies that have used monkeys to examine behavioral pharmacology [1,12,13] and drug metabolism [2,6,10], there have been few reports on immunological function. In our study, cynomolgus monkeys were given a single injection of MAP, and changes in blood cell count, biochemistry values, serum cortisone level, natural killer (NK) cell activity and the mitogen response of T-lymphocytes were investigated.…”

Computer-Assisted Video Assessment of Dyskinetic Movements

“…TD, conversely, is usually maximal when the drug is wearing off (Gardos et al, 1978), and (although this is controversial), sometimes responds well to cholinomimetics (Moore and Bowers, 1980). However, this confusion of the two side effects has led to controversial practices, because many pharmaceutical companies use the propensity of a drug to induce acute dystonic reactions in "primed" monkeys as an indication of whether a new drug will induce extrapyramidal dysfunction (Neale et al, 1984) even though it has never been demonstrated that these acute dystonic reactions are an accurate predictor of TD development. The highly fluctuating (once a week) neuroleptic regimen in primates clearly contributes to the progressive appearance of this syndrome, and it is noteworthy that humans are never persistently maintained on such an extremely fluctuating drug regimen.…”