Summary
Ro 11-2465, a selective inhibitor of serotonin uptake of the imipramine group, was examined for its central and peripheral antiserotonin activity.
Ro 11-2465 (10mg/kg) antagonized the stimulation of the hind limb flexor reflex in the spinal rat evoked by serotonin agonists of direct mode of action (LSD, quipazine, m-chlorophenylpiperazine). However, in doses up to 20 mg/kg it did not inhibit the clonidine-induced stimulation of the flexor reflex. It also reduced the number of the quipazine-induced head twitches in rats (ID50=20.1 mg/kg) and, in doses 0.3–10.0 mg/kg, dosedependently attenuated the pressor response to serotonin in the pithed rat. Like doxepine, amitriptyline, clomipramine and imipramine, Ro 11-2465 reduced the serotonin-induced contractions of the rat stomach fundus strip (itsIC50=5×10−5M).
The obtained results indicate that like other tricyclic inihibtors of serotonin uptake, Ro 11-2465 may also weakly block the postsynaptic serotonin receptors. Additional studies with fluoxetine and Org 6582 indicate that anti-serotonin properties of tricyclic compounds are not related to the serotonin uptake blocking properties.
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Andén, N.-E., Corrodi, H., Fuxe, K., Hökfelt, B., Hökfelt, T., Rydlin, C., Svensson, T.: Evidence for a central noradrenaline receptor stimulation by clonidine. Life Sci.9 (I), 513–523 (1970).
Andén, N.-E., Grabowska, M., Strömbom, U.: Different alpha-adrenoceptors in the central nervous system mediating biochemical and functional effects of clonidine and receptor blocking agents. Naunyn-Schmiedeberg's Arch. Pharmacol.292, 43–52 (1976).
Andén, N. E., Grabowska, M.: FLA 136: Selective agonist at central alphaadrenoceptors mediating changes in the turnover of noradrenaline. Naunyn-Schmiedeberg's Arch. Pharmacol.298, 239–243 (1977).
Burkard, W. P.: Specific binding sites in rat brain for a new and potent inhibitor of 5-hydroxytryptamine uptake: Ro 11-2465. Eur. J. Pharmacol.61, 409–410 (1980).
Claassen, V., Davies, J. E., Hertting, G., Placheta, P.: Fluvoxamine, a specific 5-hydroxytryptamine uptake inhibitor. Brit. J. Pharmacol.60, 505–516 (1977).
Corne, S. J., Pickering, R. W., Warner, B. T.: A method for assessing the effects of drugs on the central actions of 5-hydroxytryptamine. Brit. J. Pharmacol.20, 106–120 (1963).
Fuller, R. W., Snoddy, H. D., Perry, K. W., Bymaster, F. P., Wong, D. T.: Importance of duration of drug action in the antagonism of p-chloroamphetamine depletion of brain serotonin-comparison of fluoxetine and chlorimipramine. Biochem. Pharmac.27, 193–198 (1977).
Fuxe, K., Ögren, S.-O., Agnati, L., Gustafsson, J. A., Jonsson, G.: On the mechanism of action of the antidepressant drugs amitriptyline and nortriptyline. Evidence for 5-hydroxytryptamine receptor blocking activity. Neurosci. Letters6, 339–343 (1977).
Gillespie, J. S., Maclaren, A., Pollock, D.: A method of stimulating different segments of the autonomic outflow from the spinal column to various organs in the pithed cat and rat. Brit. J. Pharmacol.40, 257–267 (1970).
Haefely, W., Scbaffner, R., Burkard, W. P., Da Prada, M., Keller H. H., Polc, P., Richards, J. G.: Ro 11-2465, a potent and selective inhibitor of 5-hydroxytryptamine uptake. Abstract, 11th CINP Congress, Vienna, July 9–14, 1978.
Hyttel, J.: Neurochemical characterization of a new potent and selective serotonin uptake inhibitor, Lu 10-171. Psychopharmacology51, 225 to 233 (1977).
Keller, H. H., Burkard, W. P., Da Prada, M.: Dopamine receptor blockade in rat brain after acute and subchronic treatment with tricyclic antidepressants. Adv. Biochem. Psychopharmacol.24, 175–179 (1980).
Kwiatek, H., Kurleto, E., Górka, Z.: Peripheral antiserotonin activity of antidepressant drugs in rats. Abstract, Seventh Congress of the Polish Pharmacological Society, Poznań, September 25–28, 1980.
Litchfield, J. T., Wilcoxon, F.: A simplified method of evaluating doseeffect experiments. J. Pharmacol. Exp. Ther.96, 96–113 (1949).
Maj, J., Palider, W., Baran, L.: The effects of serotonergic and antiserotoninergic drugs on the flexor reflex of spinal rat: a proposed model to evaluate the action on the central serotonin receptors. J. Neural Transm.38, 131–147 (1976).
Maj, J., Gancarczyk, L., Górszczyk, E., Rawiów, A.: Doxepin as blocker of central serotonin receptors. Pharmakopsychiat.10, 318–324 (1977).
Maj, J., Lewandowska, A., Rawiów, A.: Central antiserotonin action of amitriptyline. Pharmakopsychiat.12, 281–285 (1979 a).
Maj, J., Palider, W., Rawiów, A.: Trazodon, a central serotonin antagonist and agonist. J. Neural Transm.44, 237–248 (1979 b).
Ögren, S.-O., Fuxe, K., Agnati, L. F., Gustafsson, J. A., Jonsson, G., Holm, A. C.: Reevaluation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs. J. Neural Transm.46, 85–103 (1979).
Pawlowski, L., Kwiatek, H., Ruczyńska, J.: A comparison of effects of zimelidine with those of other inhibitors of the serotonin (5-HT) uptake. In: Abstracts of the 12th CINP Congress, Göteborg, June 22–26, 1980, Progr. Neuro-Psychopharmacol., Suppl. (Radouco-Tbomas, C., Garcin, F., eds.), p. 277. Oxford: Pergamon Press. 1980.
Peroutka, S. J., Snyder, S. H.: Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Science210, 88–90 (1980).
Petersen, E. N., Olsson, S.-O., Squires, R. F.: Effects of 5-HT uptake inhibitors on the pressor response to 5-HT in the pithed rat. The significance of the 5-HT blocking property. Eur. J. Pharmacol.43, 209–215 (1977).
Rokosz-Pelc, A., Antkiewicz-Michaluk, L., Vetulani, J.: 5-Hydroxytryptamine-like properties of m-chlorophenylpiperazine: comparison with quipazine. J. Pharm. Pharmacol.32, 220–222 (1980).
Sugrue, M. F., Goodlet, I., Mireylees, S. E.: On the selective inhibition of serotonin uptake in vivo by Org 6582. Eur. J. Pharmacol.40, 121–130 (1976)
Vane, J. R.: A sensitive method for the assay of 5-hydroxytryptamine. Brit. J. Pharmacol.12, 344–349 (1957).
Wong, D. T., Horng, J. S., Bymaster, F. P., Hauser, K. L., Molloy, B. B.: A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life Sci.15, 471–479 (1974).
Wong, D. T., Bymaster, F. P., Horng, J. S., Molloy, B. B.: A new selective inhibitor for the uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. J. Pharmacol. Exp. Ther.193, 804–811 (1975).
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Pawlowski, L., Kwiatek, H. & Górka, Z. Is Ro 11-2465 (Cyan-imipramine) an antagonist of postsynaptic serotonin receptors?. J. Neural Transmission 52, 61–72 (1981). https://doi.org/10.1007/BF01253098
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DOI: https://doi.org/10.1007/BF01253098