Summary
Recent studies suggest that the antidepressant activity could be explained by gradually developing modifications in the sensitivity of some central monoaminergic receptors. As concernsα 2-receptors, some largely indirect informations suggest that a subsensitivity develops following chronic treatment with desipramine or imipramine. However it is not clear whether this effect is shared by other antidepressants. In view of the important role of these receptors in the regulation of noradrenergic neurotransmission, single cell recording and microiontophoretic techniques were used in this work to systematically assess locus coeruleus (L.C.)α 2-receptor sensitivity following acute and chronic administration of various antidepressants. The responsiveness of L.C.α 2-receptors to iontophoretically applied clonidine was studied simultaneously with the responsiveness of L.C. opiate receptors to iontophoretically applied morphine in order to test the specificity in the putative modifications induced by the antidepressants. The compounds studied were desipramine (DMI), imipramine (IMI), clomi-pramine (CIMI), zimelidine (ZIM), mianserin (MIAN), iprindole (IPR) and chlorpromazine (CPZ). Long-term treatment with DMI, IMI and ZIM but not with the other clinically effective antidepressant drugs induced a decrease in the responsiveness of L.C. neurons to iontophoretically applied clonidine. None of the drugs tested altered the responsiveness of these neurons to iontophoretically applied morphine. Consequently the therapeutic effectiveness of antidepressant drugs can not be generally related to modulation of the sensitivity of centralα 2 or opiate receptors.
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References
Aghajanian, G. K., Cedarbaum, J. M., Wang, R. Y.: Evidence for norepinephrine-mediated collateral inhibition of locus coeruleus neurons. Brain Res.136, 570–577 (1977).
Aghajanian, G. K.: Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature276, 186–188 (1978).
Atweh, S. F., Kuhar, M. J.: Autoradiographic localization of opiate receptors in rat brain. II. The brain stem. Brain Res.129, 1–12 (1977).
Banerjee, S. P., Kung, L. S., Riggi, S. J., Chanda, S. K.: Development ofβ-adrenergic receptor subsensitivity by antidepressants. Nature268, 455–456 (1977).
Baumann, P. A., Maître, L.: Blockade of the presynaptic alpha receptor in rat cortex by antidepressants. Experientia31, 726 (1975).
Baumann, P. A., Maître, L.: Blockade of presynapticα-receptors and of amine uptake in the rat brain by the antidepressant mianserine. Naunyn-Schmiedeberg's Arch. Pharmacol.300, 31–37 (1977).
Bergstrom, D. A., Kellar, K. J.: Adrenergic and serotonergic receptor binding in rat brain after chronic desmethylimipramine treatment. The J. Pharmacol. Exp. Ther.209, 256–261 (1979).
Bird, S., Kuhar, M. J.: Iontophoretic application of opiates to the locus coeruleus. Brain Res.122, 523–533 (1977).
Bloom, F., Segal, D., Ling, N., Guillemin, R.: Endorphins: profound behavioural effects in rats suggests new etiological factors in mental illness. Science194, 630–632 (1976).
Bloom, F. E., Siggins, G. R., Henriksen, S. J.: Electrophysiologic assessment of receptor changes following chronic drug treatment. Fed. Proc.40, 166 to 172 (1981).
Bunney, W. E., Jr., Post, R. M., Andersen, A. E., Kopanda, R. J.: A neuronal receptor sensitivity mechanism in affective illness (a review of evidence). Comm. Psychopharm.1, 393–405 (1977).
Carlsson, A., Corrodi, H., Fuxe, K., Hökfelt, T.: Effects of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4,α-dimethyl-meta-tyramine. Europ. J. Pharmacol.5, 367 to 373 (1969).
Carlsson, A.: The contribution of drug research to investigating the nature of endogenous depression. Pharmakopsych.9, 2–10 (1976).
Cedarbaum, J. M., Aghajanian, G. K.: Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. Europ. J. Pharmacol.44, 375–385 (1977).
Crews, F. T., Smith, C. B.: Presynaptic alpha receptor subsensitivity after long-term antidepressant treatment. Science202, 322–324 (1978).
Crews, F. T., Paul, S. M., Goodwin, F. K.: Acceleration ofβ-receptor desensitization in combined administration of antidepressants and phenoxybenzamine. Nature290, 787–789 (1981).
De Montigny, C., Aghajanian, G. K.: Tricyclic antidepressants: long-term treatment increases responsitivity of rat forebrain neurons to serotonin. Science202, 1303–1306 (1978).
Engberg, G., Svensson, T. H.: Mianserin: direct activation of brain norepine-phrine neurons by blockingα 2-receptors. Comm. Psychopharm.4, 233 to 239 (1980).
Engberg, G., Elam, M., Svensson, T. H.: Clonidine withdrawal: activation of brain noradrenergic neurons with specifically reducedα 2-receptor sensitivity. Life Sci.30, 235–243 (1982).
Fludder, J. M., Leonard, B. E.: Chronic effects of mianserin on noradrenaline metabolism in the rat brain: evidence for a presynapticα-adrenolytic actionin vivo. Psychopharmacology64, 329–332 (1979).
Garcia-Sevilla, J. A., Zis, A. P., Zelnick, T. C., Smith, C. B.: Tricyclic antidepressant drag treatment decreasesα 2-adrenoceptors on human platelet membranes. Europ. J. Pharmacol.69, 121–123 (1981).
Goodlet, J., Mireylees, S. E., Sugrue, M. F.: Effects of mianserin, a new antidepressant, onin vitro andin vivo uptake of monoamines. Br. J. Pharmacol.61, 307–313 (1977).
Graham, A. W., Aghajanian, G. K.: Effects of amphetamine on single cell activity in a catecholamine nucleus, the locus coeruleus. Nature234, 100–102 (1971).
Guyenet, P. G., Aghajanian, G. K.: A Ch, substance P and met-enkephalin in the locus coeruleus: pharmacological evidence for independent sites of action. Europ. J. Pharmacol.53, 319–328 (1979).
Horn, A. S., Coyle, J. T., Snyder, S. H.: Catecholamine uptake by synaptosomes from rat brain. Structure-activity relationship of drugs with differential effects on dopamine and norepinephrine neurons. Mol. Pharmacol.7, 66–80 (1971).
Korf, J., Bunney, B. S., Aghajanian, G. K.: Noradrenergic neurons: morphine inhibition of spontaneous activity. Europ. J. Pharmacol.25, 165–169 (1974).
McMillen, B. A., Warnack, W., German, D. C., Shore, P. A.: Effects of chronic desipramine treatment on rat brain noradrenergic responses toα-adrenergic drugs. Europ. J. Pharmacol.61, 239–246 (1980).
Menkes, D. B., Aghajanian, G. K., McCall, R. B.: Chronic antidepressant treatment enhancesα-adrenergic and serotonergic responses in the facial nucleus. Life Sci.27, 45–55 (1980).
Ogren, S. O., Ross, S. B., Hall, H., Holm, A. C., Renyi, A. L.: The pharmacology of zimelidine: a 5-HT selective reuptake inhibitor. In: Recent advances in the treatment of depression. Proc. of an intern. symp., Corfu, April 1980 (Carlsson, A., Gottfries, C. G., Holmberg, G., Modigh, K., Svensson, T., Ogren, S. O., eds.). Acta Psych. Scand., Suppl. 290, Vol. 63, pp. 127–152. 1981.
Olpe, H. R., Schellenberg, A.: Reduced sensitivity of neurons to noradrenaline after chronic treatment with antidepressant drugs. Europ. J. Pharmacol.63, 7–13 (1980).
Pert, C. B., Kuhar, M. J., Snyder, S. H.: Autoradiographic localization of the opiate receptor in rat brain. Life Sci.16, 1849–1854 (1975).
Raskin, A., Schulterbrandt, J. G., Reatig, N., Chase, C., McKeon, J. J.: Differential response to chlorpromazine, imipramine and placebo. Arch. Gen. Psychiatry23, 164–173 (1970).
Rosenblatt, J. E., Pert, C. B., Talman, J. F., Pert, A., Bunney. W. E.: The effect of imipramine and lithium onα- andβ-receptor binding in rat brain. Brain Res.160, 186–191 (1979).
Ross, S. B., Renyi, A. L., Ogren, S. O.: A comparison of the inhibitory activities of iprindol and imipramine on the uptake of 5-hydroxytryptamine and noradrenaline in brain slices. Life Sci.10, 1267–1277 (1971).
Ross, S. B., Renyi, A. L.: Tricyclic antidepressant agents. I. Comparison of the inhibition of the uptake of 3H-noradrenaline and 14C-5-hydroxytryptamine in slices and crude synaptosome preparations of the midbrain-hypothalamus region of the rat brain. Acta pharmacol. toxicol.36, 382 to 394 (1975).
Ross, S. B., Renyi, A. L.: Inhibition of neuronal uptake of 5-hydroxytryptamine and noradrenaline in rat brain by (Z)- and (E)-3-(4-bromo-phenyl)-N, N-dimethyl-3-(3-pyridil)allylamines and their secondary analogues. Neuropharmacol.16, 57–63 (1977).
Ross, S. B., Hall, H., Renyi, A. L., Westerlund, D.: Effects of zimelidine on serotonergic and noradrenergic neurons after repeated administration in the rat. Psychopharmacol.72, 219–225 (1981).
Schultz, J.: Psychoactive drug effects on a system which generates cyclic AMP in brain. Nature261, 417–418 (1976).
Schultz, J. E., Siggins, G. R., Schocker, F. W., Türck, M., Bloom, F. E.: Effects of prolonged treatment with lithium and tricyclic antidepressants on discharge frequency, norepinephrine responses and beta receptor binding in rat cerebellum: electrophysiological and biochemical comparison. J. Pharmacol. Exp. Ther.216, 28–38 (1981).
Scuvée-Moreau, J.: Contribution expérimentale à l'étude du mode d'action des substances antidépressives. Université de Liège, Thèse, 1981.
Sellinger-Barnette, M. M., Mendels, J., Frazer, A.: The effect of psychoactive drugs on beta-adrenergic receptor binding sites in rat brain. Neuropharmacol.19, 447–454 (1980).
Simmonds, M. A.: Quantitative evaluation of responses to microiontophoretically applied drugs. Neuropharmacol.13, 401–406 (1974).
Strahlendorf, H. K., Strahlendorf, J. C., Barnes, C D.: Endorphin-mediated inhibition of locus coeruleus neurons. Brain Res.191, 284–288 (1980).
Sugrue, M. F.: Effects of acutely and chronically administered anti-depressants on the clonidine-induced decrease in rat brain 3-methoxy-4-hydroxyphenylethyleneglycol sulphate content. Life Sci.28, 377–384 (1980).
Sulser, F., Vetulani, J., Mobley, P. L.: Mode of action of antidepressant drugs. Biochem. Pharmacol.27, 257 (1978).
Sulser, F.: New perspectives on the mode of action of antidepressant drugs. Trends in Neurosci., pp. 92–94. 1979.
Svensson, T. H., Bunney, B. S., Aghajanian, G. K.: Inhibition of both nor-adrenergic and serotonergic neurons in brain by theα-adrenergic agonist clonidine. Brain Res.92, 291–306 (1975).
Svensson, T. H., Usdin, T.: Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants:α-receptor mediation. Science202, 1089–1091 (1978).
Svensson, T. H., Usdin, T.: Alpha-adrenoceptor mediated inhibition of brain noradrenergic neurons after acute and chronic treatment with tricyclic antidepressants. In: Catecholamines: Basic and Clinical Frontiers (Usdin, E., Kopin, I. J., Barchas, J., eds.), pp. 672–674. New York: Pergamon Press. 1979.
Svensson, T.H., Dahlöf, C., Engberg, G., Hallberg, H.: Central pre- and post-synaptic monoamine receptors in antidepressant therapy. In: Recent Advances in the Treatment of Depression. Proc. of an intern, symp., Corfu, April 1980 (Carlsson, A., Gottfries, C. G., Holmberg, G., Modigh, K., Svensson, T., Ogren, S. O., eds.). Acta Psych. Scand., Suppl. 290, Vol. 63, pp. 67–78. 1981.
Terenius, L., Wahlström, A., Lindström, L., Widerlöv, E.: Increased CSF levels of endorphins in chronic psychosis. Neurosci. Letters3, 157–162 (1976).
Terenius, L., Wahlström, A., Agren, H.: Naloxone (Narcan®) treatment in depression: clinical observations and effects on CSF endorphins and monoamine metabolites. Psychopharmacol.54, 31–33 (1977).
U'Prichard, D. C., Enna, S. J.:In vitro modulation of CNSβ-receptor number by antidepressants andβ-agonists. Europ. J. Pharmacol.59, 297–301 (1979).
Vetulani, J., Sulser, F.: Action of various antidepressant treatments reduces reactivity of noradrenergic cyclic AMP-generating system in limbic fore-brain. Nature257, 495 (1975).
Wang, R. Y., Aghajanian, G. K.: Enhanced sensitivity of amygdaloid neurons to serotonin and norepinephrine after chronic antidepressant treatment. Comm. Psychopharm.4, 83–90 (1980).
Wiech, N. L., Ursillo, R. C.: Acceleration of desipramine-induced decrease of rat corticocerebralβ-adrenergic receptors by yohimbine. Comm. Psychopharm.4, 95–100 (1980).
Wolfe, B. B., Harden, T. K., Sporn, J. R., Molinoff, P. B.: Presynaptic modulation of beta adrenergic receptors in rat cerebral cortex after treatment with antidepressants. J. Pharmacol. Exp. Ther.207, 446–457 (1978).
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Scuvée-Moreau, J.J., Svensson, T.H. Sensitivityin vivo of centralα 2-and opiate receptors after chronic treatment with various antidepressants. J. Neural Transmission 54, 51–63 (1982). https://doi.org/10.1007/BF01249278
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DOI: https://doi.org/10.1007/BF01249278