Abstract
The effects of long-term treatment (36 weeks) with a neuroleptic drug (flupenthixol) were investigated behaviourally and biochemically in rats. Sixteen rats were trained on a DRL (differential reinforcement of low rate) 15-s schedule until stable responding was obtained. During the following 36 weeks 9 rats were injected weekly with flupenthixol dissolved in Viscoleo® [4 mg/kg (i.m.)] and seven rats received Viscoleo® alone. During this perod the animals were not run on the DRL schedule. Retesting on DRL 7 weeks after the last drug injection yielded highly significant differences between the flupenthixol-treated animals and the controls. Thorough neurological examinations of the animals just preceding the retesting period also revealed some deficits in the flupenthixol-treated animals. At sacrifice, 14–18 weeks after the last drug injection, levels of homovanillic acid (HVA) were measured in the corpus striatum and total 3-methoxy-4-hydroxyphenylglycol (MOPEG) in the rest of the forebrain. The results indicate a nonsignificant increase of 25% in the dopamine metabolite HVA, while the noradrenergic metabolite MOPEG was significantly decreased by 14% in experimental animals. The possibility of persistent functional and biochemical effects produced by prolonged treatment with a neuroleptic drug is highlighted in the results presented here.
Similar content being viewed by others
References
Ahlenius, S., Engel, J.: Effects of a dopamine (DA)-beta-hydroxylase inhibitor on timing behavior. Psychopharmacologia (Berl.) 24, 243–246 (1972)
Ahlenius, S., Brown, R., Engel, J., Lundborg, P.: Learning deficits in 4 weeks old offspring of the nursing mothers treated with the neuroleptic Penfluridol. Naunyn Schmiedebergs Arch. Pharmacol. 279, 31–37 (1973)
Ahlenius, S., Engel, J., Lundborg, P.: Antagonism by d-amphetamine of learning deficits in rats induced by exposure to antipsychotic drugs during early postnatal life. Naunyn Schmiedebergs Arch. Pharmacol. 288, 185–193 (1975)
Bræstrup, C., Andersen, H., Randrup, A.: The monoamine oxidase B inhibitor, deprenyl, potentiates phenylethylamine behaviour in rats without inhibition of catecholamine metabolite formation. Eur. J. Pharmacol. 34, 181–187 (1975)
Bræstrup, C.: Identification of free and conjugated 3-methoxy-4-hydroxyphenylglycol (MOPEG) in rat brain by gas chromatography and mass fragmentography. Anal. Biochem. 55, 420–431 (1975)
Crane, G. E.: Tardive dyskinesia in patients treated with major neuroleptics: a review of the literature. Am. J. Pschiatry 124, 40–48 (1968)
Davies, O. L.: The design and analysis of industrial experiments, p. 26. London: Oliver and Boyd 1960
Davies, J. A., Jackson, B., Redfern, P. H.: The effect of anti-parkinsonian drugs on haloperidol-induced inhibition of the conditioned avoidance response in rats. Neuropharmacology 12, 735–740 (1973)
Davies, J. A., Redfern, P. H.: The effect of dopamine-antagonists and amantadine on the acquisition of the conditioned avoidance response in rats. J. Pharm. Pharmacol. 25 [suppl. 128] (1973)
Ferster, C. B., Skinner, B. F.: Schedules of reinforcement. New York: Appleton-Century-Crofts 1958
Fog, R., Pakkenberg, H., Juul, P., Bock, E., Jørgensen O. S., Andersen, J.: High-dose treatment of rats with perphenazine enanthate. Psychopharmacology 50, 305–307 (1977)
Gerlach, J., Thorsen, K.: The movement pattern of oral tardive dyskinesia in relation to anticholinergic and antidopaminergic treatment. Int. Pharmacopsychiatry 11, 1–7 (1976)
György, L., Pfeifer, K. A., Hagtman, B.: Modification of certain central nervous effects of haloperidol during long-term treatment in the mouse and rat. Psychopharmacologia (Berl.) 16, 223–233 (1969)
Jackson, D. M., Andén, N. E., Engel, J., Liljequist, S.: The effect of long-term penfluridol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens and in the corpus striatum. Psychopharmacologia (Berl.) 45, 151–155 (1975)
Janssen, P. A. J., Niemegeers, C. J. E., Schellekens, K. H. L., Dresse, A., Lenaerts, F. M., Pinchard, A. Schaper, V. K. A., Van Nueten, J. M., Verbruggen, F. J.: Pimozide, a chemically novel, highly potent and orally long-acting neuroleptic drug. Arzneim. Forsch. 18, 261–288 (1968)
Janssen, P. A. J., Niemegeers, C. J. E., Schellekens, K. H. L., Lenaerts, F. M., Verbruggen, F. J., Van Nueten, J. A., Schaper, W. K. A.: The pharmacology of penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug. Eur. J. Pharmacol. 11, 139–154 (1970)
Jørgensen, A., Fredricson, K., Overø, Hansen, V.: Metabolism, distribution and excretion of flupenthixol decanoate in dogs and rats. Acta Pharmacol. Toxicol. 29, 339–358 (1971)
Lyon, M., Randrup, A.: The dose-response effect of amphetamine upon avoidance behaviour in the rat seen as function of increasing stereotypy. Psychopharmacologia (Berl.) 23, 334–347 (1972)
Lyon, M., Robbins, T.: The action of central nervous system stimulant drugs: a general theory concerning amphetamine. Pharmacology2. New York: Spectrum Publications Inc. 1975
Møller-Nielsen, I., Pedersen, V., Nymark, M., Franck, K. F., Boeck, V., Fjalland, B., Christensen, A. V.: The comparative pharmacology of flupenthixol and some reference neuroleptics. Acta Pharmacol. Toxicol. 33, 353–362 (1973)
Møller-Nielsen, J., Fjalland, B., Pedersen, V., Nymark, M. Pharmacology of neuroleptics upon repeated administration. Psychopharmacologia (Berl.) 34, 95–104 (1974)
Nymark, M., Franck, K. F., Pedersen, V., Boeck, V., Møller-Nielsen, I.: Prolonged neuroleptic effect of α-Flupenthixol decanoate in oil. Acta Pharmacol. Toxicol. 33, 363–376 (1973)
Pakkenberg, H., Fog, R., Nilakantan, B.: The long-term effect of perphenazine enanthate on the rat brain. Some metabolic and anatomical observations. Psychopharmacologia (Berl.) 29, 329–336 (1973)
Roffler-Tarlov, S., Sharman, D. F., Tegerdine, P.: 3,4-Dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid in the mouse striatum: a reflection of intra-and extra-neuronal metabolism of dopamine? Br. J. Pharmacol. 42, 343–351 (1971)
Von Voightlander, P. F.: Behavioral and biochemical investigation of dopamine supersensitivity induced by chronic neuroleptic treatment. Fed. Proc. 33, 578 (1974)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nielsen, E.B. Long-term behavioural and biochemical effects following prolonged treatment with a neuroleptic drug (flupenthixol) in rats. Psychopharmacology 54, 203–208 (1977). https://doi.org/10.1007/BF00426781
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00426781