Summary
It was observed that rats that had been given drugs that enhance serotonergic neurotransmission,e.g. the serotonin releasing compounds p-chloroamphetamine (PCA) and fenfluramine, the MAO-A inhibitors and serotonin releasing agents amiflamine andα-ethyltryptamine and the serotonin agonists 5-methoxy-N, N-dimethyltryptamine (5-MeODMT), 8-hydroxy-2-(di-n-propylamino) tetraline (8-OH-DPAT), m-chlorophenyl piperazine (m-CPP) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl)1H-indole (RU 24969), did not leave their home-cages when the grid-covers were removed in contrast to normal rats who almost immediately left the cages. The association between the serotonin neurotransmission and the inhibitory effect of PCA on the cage-leaving response was indicated by the findings that 1. Serotonin uptake inhibitors (alaproclate and citalopram) antagonized the effect of PCA. 2. High, neurotoxic doses of PCA antagonized the effect of PCA when tested one week after the former administration. The serotonin uptake inhibitor zimeldine counteracted the effect of neurotoxic PCA. 3. Depletion of brain serotonin with p-chlorophenylalanine counteracted the effect of acute PCA. 4. Repeated treatment of rats for 7 days with zimeldine, amiflamine,α-ethyltryptamine or clorgyline plus a low dose of PCA counteracted the effect of acute PCA probably due to a functional downregulation at postsynaptic receptors. Clorgyline or a low dose of PCA by themselves had no effect. 5. Compounds interacting with dopamine or noradrenaline mechanisms,e.g. α-methyltyrosine, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP 4), pimozide, remoxipride and prazosin did not antagonize the effect of PCA nor did (+)-amphetamine inhibit the cageleaving response. None of the serotonin receptor antagonists (cinanserin, ketanserin, metergoline, methysergide, metitepine, mianserin, pirenperone) blocked the inhibition of the cage-leaving response produced by PCA, indicating that the receptors involved may not be of the S1 and S2-types. Observation of the cage-leaving response may be a valuable technique in studies of drugs that enhance the serotonin neurotransmission in the rat brain.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahlenius, S., Larsson, K.: Failure to antagonize the 8-hydroxy-2-(di-n-propylamino)tetralin-induced facilitation of male rat sexual behavior by administration of 5-HT receptor antagonists. Eur. J. Pharmac.99, 279–286 (1984).
Archer, T.: Serotonin and fear retention in the rat. J. comp. physiol. Psychol.96, 491–516 (1982).
Archer, T., ögren, S.-O., Johansson, C.: The acute effect of p-chloroamphetamine on the retention of fear conditioning in the rat: Evidence for a role of serotonin in memory consolidation. Neurosci. Lett.25, 75–81 (1981).
Archer, T., ögren, S.-O., Ross, S. B.: Serotonin involvement in aversive conditioning: reversal of the fear retention deficit by long-term p-chloroamphetamine but not p-chlorophenylalanine. Neurosci. Lett.34, 75–82 (1982).
Archer, T., Tandberg, B., Rényi, L., Ross, S. B.: Antagonism of 5-methoxy-N,N-dimethyltryptamine-induced changes of postdecapitation convulsions by repeated treatment with drugs enhancing serotonin neurotransmission. J. Pharm. Pharm., in press (1985).
Ask, A.-L., Fagervall, I., Ross, S. B.: Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain. Naunyn-Schmiedebergs Arch. Pharmacol.324, 79–87 (1983).
Baumann, P. A., MaÎtre, L.: Neurobiochemical aspects of maprotiline (Ludiomile®) action. J. Int. Med. Res.7, 391–400 (1979).
Fuller, R. W., Perry, K. W., Molloy, B. B.: Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine. Eur. J. Pharmacol.33, 119–124 (1975).
Fuxe, K., Holmstedt, B., Jonsson, G.: Effects of 5-methoxy-N,N-dimethyltryptamine on central monoamine neurons. Eur. J. Pharmacol.19, 25–34 (1972).
Fuxe, K., ögren, S. O., Agnati, L. F.: The effects of chronic treatment with the 5-hydroxytryptamine uptake blocker zimeldine on central 5-hydroxytryptamine mechanisms. Evidence for the induction of a low affinity binding site of 5-hydroxytryptamine. Neurosci. Lett.13, 307–312 (1979).
Goodwin, G. M., Green, A. R.: A behavioural and biochemical study in mice and rats of putative selective agonists and antagonists for 5-HT1 and 5-HT2 receptors. Br. J. Pharmac.84, 743–753 (1985).
Göthert, M.: Modulation of serotonin release in the brain via presynaptic receptors. Trends Pharmacol. Sci.4, 437–440 (1982).
Grahame-Smith, D.-G.: Inhibitory effect of chlorpromazine on the syndrome of hyperactivity produced by L-tryptophan or 5-methoxy-N,N-dimethyltryptamine in rats treated with a monoamine oxidase inhibitor. Br. J. Pharmacol.43, 856–864 (1971).
Green, A. R., Heal, D. J.: The effects of drugs on serotonin-mediated behavioural models. In: Neuropharmacology of Serotonin (Green, A. R., ed.), pp. 326–365. Oxford: University Press. 1985.
Green, A. R., Guy, A. P., Gardner, C. R.: The behavioural effects of RU 24969, a suggested 5-HT1 receptor agonist in rodents and the effect on the behaviour of treatment with antidepressants. Neuropharmacology23, 655–661 (1984).
Haigler, H. J., Aghajanian, G. K.: Peripheral serotonin antagonists: Failure to antagonize serotonin in brain areas receiving a prominent serotonergic input. J. Neural Transm.35, 257–273 (1974).
Hall, H., Ross, S. B., ögren, S.-O.: Effects of zimelidine on various transmitter systems in the brain. In: Typical and Atypical Antidepressants: Molecular Mechanisms (Costa, E., Racagni, G., eds.), pp. 321–325. New York: Raven Press. 1982.
Hall, H., Ross, S. B., SÄllemark, M.: Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants onΒ-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex. J. Neural Transm.59, 9–23 (1984).
Hjorth, S., Carlsson, A., Lindberg, P., Sanchez, D., Wikström, H., Arvidsson, L.-E., Hacksell, V., Nilsson, J. L. G.: 8-Hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity. J. Neural Transm.55, 169–188 (1982).
Hunt, P. J., Oberlander, C.: The interaction of indole derivatives with the serotonin receptor and non-dopaminergic circling behaviour. In: Serotonin-Current Aspects of Neurochemistry (Haber, B., ed.), pp. 547–562. New York: Plenum Press. 1981.
Hyttel, J.: Citalopram—a pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog. Neuro-Psychopharmacol. Biol. Psychiat.6, 277–295 (1982).
Jonsson, G., Hallman, H., Ponzio, F., Ross, S.: DSP 4-(N-2-chloroethyl-N-ethyl-2-bromobenzylamine)—a useful denervation tool for central and peripheral noradrenaline neurons. Eur. J. Pharmacol.72, 173–188 (1981).
Kirk, R. E.: Experimental Design: Procedures for the Behavioral Sciences. Brook/Cole (1968).
Köhler, C., Ross, S. B., Srebro, B., ögren, S. O.: Long-term biochemical and behavioural effects of p-chloroamphetamine in the rat. Ann. N. Y. Acad. Sci.305, 645–663 (1978).
Lakoski, J. M., Aghajanian, G. K.: Effects of ketanserin on neuronal responses to serotonin in the prefrontal cortex, lateral geniculate and dorsal raphe nucleus. Neuropharmacology24, 265–273 (1985).
Lindberg, U. H., Thorberg, S. O., Bengtsson, S., Rényi, A. L., Ross, S. B., ögren, S. O.: Inhibitors of neuronal monoamine uptake, 2. Selective inhibition of 5-hydroxytryptamine uptake byα-aminoacid esters of phenethylalcohols. J. Med. Chem.21, 448–456 (1978).
Lucki, I., Nobler, M. S., Frazer, A.: Differential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat. J. Pharmacol. Exp. Ther.228, 133–139 (1983).
ögren, S. O.: Forebrain serotonin and avoidance learning: behavioural and biochemical studies on the acute effect of p-chloroamphetamine on one-way active avoidance learning in the male rat. Pharmacol. Biochem. Behav.16, 881–895 (1982).
ögren, S. O., Ross, S. B., Holm, A. C., Baumann, L.: 5-Hydroxytryptamine and avoidance performance in the rat. Antagonism of the acute effect of p-chloroamphetamine by zimelidine, an inhibitor of 5-hydroxytryptamine uptake. Neurosci. Lett.7, 331–336 (1977).
ögren, S. O., Hall, H., Köhler, C., Magnusson, O., Lindbom, L.-O., Ängeby, K., Florvall, L.: Remoxipride, a new potential antipsychotic compound with selective anti-dopaminergic actions in the rat brain. Eur. J. Pharmac.102, 459–474 (1984).
Pawlowsky, L., Przegalinski, E., Hano, J.: Antiserotonergic and antidopaminergic action of pirenperone, a new S2-serotonin receptor antagonist. Naunyn-Schmiedebergs Arch. Pharmacol.324, R20 (1983).
Rényi, L.: Blockade of the serotonin syndrome induced by 5-methoxy-N,N-dimethyltryptamine after repeated treatment of rats with amiflamine and some other monoamine oxidase inhibitors. Collegium Internationale Neuro-Psychopharmacologium 14th C.I.N.P. Congress, Florence, Abstract, p. 93 (1984).
Rényi, L.: Ejaculations induced by p-chloroamphetamine in the rat. Neuropharmacology24, 697–704 (1985).
Rényi, L., Ross, S. B.: Effects of amiflamine and related compounds on the accumulation of biogenic monoamines in rat brain slicesin vitro andex vivo in relation to their behavioural effects. Acta pharmac. toxic.56, 416–426 (1985).
Ross, S. B.: Antagonism of the acute and long-term biochemical effects of 4-chloroamphetamine on the 5-HT neurons in the rat brain by inhibitors of the 5-hydroxytryptamine uptake. Acta pharmac. toxic.39, 456–476 (1976 a).
Ross, S. B.: Long-term effects of N-2-chloroethyl-N-ethyl-2-bromo-benzylamine hydrochloride on noradrenergic neurones in the rat brain and heart. Br. J. Pharmac.58, 521–527 (1976 b).
Samanin, R., Mennini, T., Ferraris, A., Bendotti, C., Borsini, F., Garattini, S.: m-Chlorophenylpiperazine: a central serotonin agonist causing powerful anorexia in rats. Naunyn-Schmiedebergs Arch. Pharmacol.308, 159–163 (1979).
Sanders-Bush, E., Steranka, L. R.: Immediate and long-term effects of p-chloroamphetamine on brain amines. Ann. N. Y. Acad. Sci.305, 208–221 (1978).
Snedecor, G. W., Cochran, W.: Statistical Methods. Ames, Iowa: The Iowa State University Press. 1967.
Trulson, M. E., Jacobs, B. L.: Behavioural evidence for the rapid release of CNS serotonin by PCA and fenfluramine. Eur. J. Pharmac.36, 149–154 (1976).
Wang, R. Y., Aghajanian, G. K.: Inhibition of neurons in the amygdala by dorsal raphe stimulation: mediation through a direct serotonergic pathway. Brain. Res.120, 85–102 (1977).
Yap, C. Y., Taylor, D. A.: Involvement of 5-HT2 receptors in the wet-dog shake behaviour induced by 5-hydroxytryptophan in the rat. Neuropharmacology20, 801–804 (1983).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rényi, L., Archer, T., Minor, B.G. et al. The inhibition of the cage-leaving response—A model for studies of the serotonergic neurotransmission in the rat. J. Neural Transmission 65, 193–210 (1986). https://doi.org/10.1007/BF01249082
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF01249082