Modification of the tremorigenic activity of physostigmine

Abstract

Drugs which reduce central catecholamine activity increased the tremorigenic action of physostigmine (025 mg/kg) in the rat. The potentiation of physostigmine tremor induced by these neuroleptic drugs was quantitated by measuring the ratio of post-to prephysostigmine motor activity; this ratio may be a useful index of catecholamine/cholinergic balance. Of the compounds tested, chlorpromazine HCI (15 mg/kg) and reserpine (10 mg/ kg) had the greatest potentiating effect on the tremor-producing action of physostigmine. L-DOPA (500 mg/kg) reduced the tremor induced by physostigmine in rats pre-treated with reserpine, but not in rats pre-treated with chlorpromazine.Normal extrapyramidal function may depend upon a sensitive balance between inhibitory dopaminergic neurones and excitatory cholinergic fibres in the basal ganglia (McGeer, Boulding, Gibson & Foulkes, 1961;Barbeau, 1962). Large doses of the acetyicholinesterase inhibitor, physostigmine, produce tremors in animals, presumably by increasing acetylcholine levels in the basal ganglia (Frances & Jacob, 1971). In patients with Parkinson's disease, physostigmine aggravates tremor, rigidity, and hypokinesia at a dose which has no neurological effects in normal subjects (Duvoisin, 1967;Weintraub & Van Woert, 1971;Van Woert & Weintraub, 1971). Anticholinergic drugs and L-dihydroxyphenylalanine (L-DOPA) clinically improve this disease and reduce or prevent the adverse neurological effects of physostigmine (Duvoisin, 1967;Weintraub & Van Woert, 1971;Van Woert & Weintraub, 1971). If the hypersensitivity to physostigmine in Parkinson's disease is due to decreased brain dopamine (Ehringer & Hornykiewicz, 1960), drugs whilch alter dopamine metabolism might also affect the neurological response to physostigmine.Recent studies in our laboratory demonstrated that serial intracisternal injections of 6-hydroxydopamine in dogs produced hypokinesia and frequently rigidity and tremor which were aggravated by intravenous physostigmine and reversed by L-DOPA and benztropine (Van Woert, Amibani & Bowers (1972) in press). We suggested that the physostigmine hypersensitivity induced' by 6-hydroxydopamine was due to the degeneration of catecholamine containing neurones produced by this amine.This communication describes the results of further experiments in rats designed to correlate the tremorigenic activity of physostigmine with drug-induced changes in catecholamine metabolism. We were particularly interested in the effect of drugs which, produce Parkinsonism such as reserpine, phenothiazines, and haloperidol on physostigmine tremor.Methods. -152 Sprague-Dawley rats weighing 180 to 220 g were used in the experiments. Tremor and motor activity were measured on a 501 activity platform (Lafayette Instruments, Lafayette, Indiana) set at a sensitivity adjustment of 10 which minimized counts due to exploratory movements, but still recorded tremor. Two rats were placed on the activity platform at one time for each measurement. After a 3 min period to permit the rats to familiarize themsel...

The Pharmacology of Rauwolfia Alkaloids

“…Antiparkinsonian drugs of the centrally active anticholinergic type, such as hyoscine, benactyzine, benzhexol, benztropine and caramiphen, abolish completely the stereotyped behaviour in reserpine-treated rats (KRUGER and RANDRUP, 1968). Benztropine reduces tremors induced by physostigmine in reserpinepretreated and chlorpromazine-pretreated rats, whereas dopa is effective only in reserpine-pretreated rats (AMBANI and WOERT, 1972). These observations may be related to the effects of reserpine on brain acetylcholine (see Section V A).…”

“…Similar stereotyped behaviour characterized by locomotion, rearing, sniffing and gnawing is also produced by oxotremorine and other cholinergic drugs such as arecoline and physostigmine in reserpine-sedated rats (KRUGER and RANDRUP, 1968;AMBANI and WOERT, 1972). Antiparkinsonian drugs of the centrally active anticholinergic type, such as hyoscine, benactyzine, benzhexol, benztropine and caramiphen, abolish completely the stereotyped behaviour in reserpine-treated rats (KRUGER and RANDRUP, 1968).…”