Summary
Mice, administered haloperidol 3 mg/kg/day, in their drinking water for 21 days, were tested for their responsiveness to cholinergic and anticholinergic drugs 4 days after withdrawal from haloperidol (or vehicle). Haloperidol-treated animals administered methylhyoscine (1 mg/kg i.p.) and various doses of physostigmine (5 to 1215μg/kg) displayed significantly less depression of locomotor activity than vehicle-treated animals. Atropine, 5 mg/kg, whilst ineffective in producing locomotor stimulation in vehicle-treated animals, produced marked stimulation in haloperidol-treated animals. Methylatropine (5 mg/kg) did not produce significant stimulation in either group. Dopamine receptor supersensitivity was present in these animals as haloperidol-treated mice, pretreated withα-methyl-tyrosine and reserpine, displayed a significantly greater locomotor response to apomorphine than did vehicle-treated animals. The data support the hypothesis that long-term administration of haloperidol produces an apparent hyposensitivity of central muscarinic receptors.
Similar content being viewed by others
References
Bartholini, G., Stadler, H., Lloyd, K. G.: Cholinergic-dopaminergic relation in different brain structures. In: Frontiers in Catecholamine Research (Usdin, E., Snyder, S., eds.), pp. 741–745. Oxford: Pergamon Press. 1973.
Carlton, P. L.: Augmentation of the behavioural effects of amphetamine by scopolamine. Psychopharmacol.2, 377–380 (1961).
Carlton, P. L., Didamo, P.: Augmentation of the behavioural effects of amphetamine by atropine. J. Pharmacol. Exp. Ther.132, 91–96 (1961).
Davis, W. M., Pinkerton, J. T.: Synergism by atropine of central stimulant properties of phenylpropanolamine. Toxicol. Applied Pharmacol.22, 138–145 (1972).
Dunstan, R., Jackson, D. M.: The demonstration of a change in adrenergic receptor sensitivity in the central nervous system of mice after withdrawal from long-term treatment with haloperidol. Psychopharmacol.48, 105–114 (1976).
Dunstan, R., Jackson, D. M.: The effect of apomorphine and clonidine on locomotor activity in mice after long-term treatment with haloperidol. Clin. Exp. Pharmacol. Physiol. (in press, 1977).
Engel, J., Liljeqvist, S., Johannessen, K.: Behavioural effects of long-term treatment with antipsychotic drugs. In: Antipsychotic Drugs, Pharmacodynamics and Pharmacokinetics (Sedvall, G., Uvnäs, B., eds.). Oxford: Pergamon Press. 1976, in press.
Fann, W. E., Lake, C. R.: The coexistence of parkinsonism and tardive dyskinesia. Dis. Nerv. Sys.35, 324–326 (1974).
Fann, W. E., Lake, C. R., Gerber, C. J., McKenzie, G. M.: Cholinergic suppression of tardive dyskinesia. Psychopharmacol.37, 101–107 (1974).
Glanutsos, G., Lal, H.: Alteration in the action of cholinergic and anticholinergic drugs after chronic haloperidol: indirect evidence for cholinergic hyposensitivity. Life Sci.18, 515–520 (1976).
Jackson, D. M.: The interaction betweenβ-phenylethylamine and agents which affect the cholinergic nervous system on locomotor activity and toxicity in mice. Arzneimittel-Forsch.24, 24–27 (1974).
Jackson, D. M., Andén, N.-E., Engel, J., Liljeqvist, S.: The effect of longterm penfluridol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens and in the corpus striatum. Psychopharmacol.45, 151–155 (1975).
Jackson, D. M., Dunstan, R., Bracs, P. U.: Pharmacological models in tardive dyskinesia: a role for dopamine and noradrenaline? In: Symposium of Drugs and Society (Johnson, G. F. S., ed.). Sydney: CIBA-Geigy. 1977, in press.
Klawans, H. L., Jr.: The parmacology of tardive dyskinesias. American J. Psychiatry130, 82–86 (1973).
Klawans, H. L., jr., Rubovits, R.: An experimental model of tardive dyskinesia. J. Neural Transmission33, 235–246 (1972).
Mennear, J. H.: Interactions between central cholinergic agents and amphetamine in mice. Psychopharmacol.7, 107–114 (1965).
Overstreet, D. H.: Reduced behavioural effects of pilocarpine during chronic treatment with DFP. Behavioural Biol.11, 49–58 (1974).
Overstreet, D. H., Kozar, M. D., Lynch, G. S.: Reduced hypothermic effects of cholinomimetic agents following chronic anticholinesterase treatment. Neuropharmacol.12, 1017–1032 (1973).
Russell, R. W., Vasquez, B. J., Overstreet, D. H., Dalglish, F. W.: Effects of cholinolytic agents on behaviour following development of tolerance to low cholinesterase activity. Psychopharmacol.20, 32–41 (1971).
Sayers, A. C., Bürki, H. R., Ruch, W., Asper, H.: Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacol.41, 97–104 (1975).
Schelkunov, E. L.: Adrenergic effect of chronic administration of neuroleptics. Nature214, 1210–1213 (1967).
Snyder, S. H.: Putative neurotransmitters in the brain: selective neuronal uptake, subcellular localisation, and interactions with centrally acting drugs, Biol. Psychiatry2, 367–389 (1970).
Snyder, S. H., Greenberg, D., Yamamura, H. I.: Antischizophrenic drugs and brain cholinergic receptors. Affinity for muscarinic sites predicts extrapyramidal effects. Arch. gen. Psychiatry31, 58–61 (1974).
Tarsy, D., Baldessarini, R. J.: Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacol.13, 927–940 (1974).
Thornburg, J. E., Moore, K. E.: Inhibition of anticholinergic drug-induced locomotor stimulation in mice byα-methyltyrosine. Neuropharmacol.12, 1179–1185 (1973).
Voigtlander, P. F. von, Losey, E. G., Triezenberg, H. J.: Increased sensitivity to dopaminergic agents after chronic neuroleptic treatment. J. Pharmacol. Exp. Ther.193, 88–94 (1975).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dunstan, R., Jackson, D.M. The demonstration of a change in responsiveness of mice to physostigmine and atropine after withdrawal from long-term haloperidol pretreatment. J. Neural Transmission 40, 181–189 (1977). https://doi.org/10.1007/BF01300132
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01300132