Summary
A range of established and putative antidepressant therapies were studied for the effect of their long-term administration on two facets of presynaptic monoaminergic functioning in rat brain, namely NE, DA, and 5-HT turnover and alpha2-adrenoceptor sensitivity. Unless stated otherwise drugs (10 mg/kg) were injected i.p. twice daily for 14 days. ECT (100 mA for 1 s) was applied once daily for 10 days.
Changes in turnover were indirectly assessed by measuring levels of metabolites. Brain levels of MHPG-SO4 were unchanged by chronic amitriptyline, imipramine, nisoxetine (20 mg/kg), nortriptyline, salbutamol (5 mg/kg), and ECT. Amitriptyline elicited a slight, but significant, increase in brain DOPAC content. Brain levels of 5-HIAA were increased by amitriptyline, imipramine, salbutamol, and ECT. An overall view of the results indicates that no common pattern of change was elicited by the range of antidepressant therapies studied.
Central alpha2-adrenoceptor sensitivity was assessed by investigating the effect of various therapies on the ability of clonidine (25μg/kg i.p.) to decrease rat brain MHPG-SO4 content. The clonidine-induced fall was attenuated by desipramine, imipramine, and ECT. Amitriptyline, iprindole, mianserin, nisoxetine, nortriptyline, Org 6582 (10 mg/kg once daily), pargyline (25 mg/kg once daily), salbutamol, and trazodone were ineffective.
The following chronic antidepressant therapies were investigated for their effect on rat frontal cortex3H-clonidine binding: amitriptyline, desipramine, imipramine, iprindole, mianserin, nisoxetine, nortriptyline, pargyline, salbutamol, and ECT. Chronic, but not acute, pargyline decreased3H-clonidine binding and this was due to a diminished number of binding sites.
The induction of subsensitive presynaptic alpha2-adrenoceptors in rat brain is not a property common to all forms of antidepressant therapies. Hence it cannot be the fundamental mode of action of antidepressants. No correlation exists between the changes in rat cortical3H-clonidine binding and the observed changes in the sensitivity of central presynaptic alpha2- adrenoceptors.
Similar content being viewed by others
References
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 drugs. Naunyn-Schmiedeberg's Arch. Pharmacol.292, 43–52 (1976).
Brodie, B. B., Shore, P. A.: A concept for a role of serotonin and norepinephrine as chemical mediators in the brain. Ann. N.Y. Acad. Sci.66, 631–642 (1957).
Brunello, N., Barbaccia, M. L., Chuang, D.-M., Costa, E.: Down-regulation of beta-adrenergic receptors following repeated injections of desmethyl-imipramine: permissive role of serotonergic axons. Neuropharmacol.21, 1145–1149 (1982).
Bylund, D. B., Snyder, S. H.:Beta adrenergic receptor binding in membrane preparations from mammalian brain. Mol. Pharmacol.12, 568–580 (1976).
Cerrito, F., Raiteri, M.: Supersensitivity of central noradrenergic presynaptic autoreceptors following chronic treatment with the antidepressant mianserin. Europ. J. Pharmacol.70, 425–426 (1981).
Cohen, R. M., Aulakh, C. S., Campbell, I, C., Murphy, D. L.: Functional subsensitivity of alpha2-adrenoceptors accompanies reductions in yohimbine binding after clorgyline treatment. Europ. J. Pharmacol.81, 145–148 (1982 a).
Cohen, R. M., Campbell, I. C., Cohen, M. R., Torda, T., Pickar, D., Siever, L. J., Murphy, D. L.: Presynaptic noradreneric regulation during depression and antidepressant drug treatment. Psychiat. Res.3, 93–105 (1980).
Cohen, R. M., Ebstein, R. P., Daly, J. W., Murphy, D. L.: Chronic effects of a monoamine oxidase-inhibiting antidepressant: decreases in functional alpha-adrenergic autoreceptors precede the decrease in norepinephrinestimulated cyclic adenosine 3′∶5′-monophosphate systems in rat brain. J. Neurosci.2, 1588–1595 (1982 b).
Coppen, A.: The biochemistry of affective disorders. Br. J. Psychiat.113, 1237–1264 (1967).
Daniel, W., Adamus, A., Melzacka, M., Szymura, J., Vetulani, J.: Cerebral pharmacokinetics of imipramine in rats after single and multiple dosages. Naunyn-Schmiedeberg's Arch. Pharmacol.317, 209–213 (1981).
Dausse, J.-P., Le Quan-Bui, K. H., Meyer, P.: Alpha1- and alpha2-adrenoceptors in rat cerebral cortex: effect of neonatal treatment with 6-hydroxydopamine. Europ. J. Pharmacol.78, 15–20 (1982).
Davis, M., Menkes, D. B.: Tricyclic antidepressants vary in decreasing alpha2adrenoceptor sensitivity with chronic treatment: assessment with clonidine inhibition of acoustic startle. Br. J. Pharmacol.77, 217–222 (1982).
Delini-Stula, A., Baumann, P., Büch, O.: Depression of exploratory activity by clonidine in rats as a model for the detection of relative pre- and post-synaptic central noradrenergic receptor selectivity of alpha-adrenolytic drugs. Naunyn-Schmiedeberg's Arch. Pharmacol.307, 115–122 (1979).
Evans, J. P. M., Grahame-Smith, D. G., Green, A. R., Tordoff, A. F. C.: Electroconvulsive shock increases the behavioural responses of rats to brain 5-hydroxytryptamine accumulation and central nervous system stimulant drugs. Br. J. Pharmacol.56, 193–199 (1976).
Fludder, J. M., Leonard, B. E.: The effects of amitriptyline, mianserin, phenoxybenzamine, and propranolol on the release of noradrenaline in the rat brainin vivo. Biochem. Pharmacol.28, 2333–2336 (1979).
Górka, Z., Zacny, E.: The effect of single and chronic administration of imipramine on clonidine-induced hypothermia in the rat. Life Sci.28, 2847–2854 (1981).
Hallberg, H., Almgren, O., Svensson, T. H.: Increased brain serotonergic and noradrenergic activity after repeated systemic administration of the beta2-adrenoceptor agonist salbutamol, a putative antidepressant drug. Psychopharmacol.73, 201–204 (1981).
Harden, T. K., Mailman, R. B., Mueller, R. A., Breese, G. R.: Noradrenergic hyperinnervation reduces the density of beta-adrenergic receptors in rat cerebellum. Brain Res.166, 194–198 (1979).
Heal, D. J., Akagi, H., Bowdler, J. M., Green, A. R.: Repeated electroconvulsive shock attenuates clonidine-induced hypoactivity in rodents. Europ. J. Pharmacol.75, 231–237 (1981).
Janowsky, A., Okada, F., Manier, D. H., Applegate, C. D., Sulser, F., Steranka, L. R.: Role of serotonergic input in the regulation of the beta-adrenergic receptor-coupled adenylate cyclase system. Science218, 900–901 (1982).
Lebrecht, U., Nowak, J. Z.: Effect of single and repeated electroconvulsive shock on serotonergic system in rat brain-I Metabolic studies. Neuropharmacol.19, 1049–1053 (1980).
Leonard, B. E.: Current status of the biogenic amine theory of depression. Neurochemistry International4, 339–350 (1982).
Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, R. J.: Protein measurement with the Folin phenol reagent. J. Biol. Chem.193, 265–275 (1951).
Maggi, A., U'Prichard, D. C., Enna, S. J.: Differential effects of antidepressant treatment on brain monoaminergic receptors. Europ. J., Pharmacol.61, 91–98 (1980 a).
Maggi, A., U'Prichard, D. C., Enna, S. J.: Beta-adrenergic regulation of alpha2-adrenergic receptors in the central nervous system. Science207, 645–647 (1980 b).
McMillen, B. A., Warnack, W., German, D. C., Shore, P. A.: Effects of chronic desipramine treatment on rat brain noradrenergic responses to alphaadrenergic drugs. Europ. J. Pharmacol.61, 239–246 (1980).
Modigh, K.: Long-term effects of electroconvulsive shock therapy on synthesis turnover and uptake of brain monoamines. Psychopharmacol.49, 179–185 (1976).
Mogilnicka, E.: The effects of acute and repeated treatment with salbutamol, a beta-adrenoceptor agonist, on clonidine-induced hypoactivity in rats. J. Neural Transm.53, 117–126 (1982).
Nagy, A.: Blood and brain concentrations of imipramine, clomipramine and their monomethylated metabolites after oral and intramuscular administration in rats. J. Pharm. Pharmac.29, 104–107 (1977).
Schildkraut, J. J.: The catecholamines hypothesis of affective disorders: a review of supporting evidence. Am. J. Psychiat.122, 509–522 (1965).
Scuvée-Moreau, J. J., Svensson, T. H.: Sensitivityin vivo of central alpha2- and opiate receptors after chronic treatment with various antidepressants. J. Neural Transm.54, 51–63 (1982).
Spyraki, C., Fibiger, H. C.: Functional evidence for subsensitivity of noradrenergic alpha2-receptors after chronic desipramine treatment. Life Sci.27, 1863–1867 (1980).
Stanford, C., Nutt, D. J., Cowen, P. J.: Comparison of the effects of chronic desmethylimipramine administration on alpha2- and beta-adren-oceptors in different regions of rat brain. Neuroscience8, 161–164 (1983).
Sugrue, M. F.: Changes in rat brain monoamine turnover following chronic antidepressant administration. Life Sci.26, 423–429 (1980 a).
Sugrue, M. F.: The inability of chronic fluoxetine to potentiate a serotonin mediated effect. Comm. Psychopharm.4, 131–134 (1980 b).
Sugrue, M. F.: The inability of chronic mianserin to block central alpha2- adrenoceptors. Europ. J. Pharmacol.68, 377–380 (1980 c).
Sugrue, M. F.: Current concepts on the mechanisms of action of antidepressant drugs. Pharmacol. Ther.13, 219–247 (1981 a).
Sugrue, M. F.: Effects of acutely and chronically administered antidepressants on the clonidine-induced decrease in rat brain 3-methoxy-4-hydroxyphenylethyleneglycol sulphate content. Life Sci.28, 377–384 (1981b).
Sugrue, M. F.: A study of the sensitivity of rat brain alpha2-adrenoceptors during chronic antidepressant treatments. Naunyn-Schmiedeberg's Arch. Pharmacol.320, 90–96 (1982).
Sugrue, M. F.: Chronic antidepressant therapy and associated changes in central monoaminergic receptor functioning. Pharmacol. Ther.21, 1–33 (1983 a).
Sugrue, M. F.: Do antidepressants possess a common mechanism of action? Biochem. Pharmacol.32, 1811–1817 (1983 b).
Sugrue, M. F., Goodlet, I., Mireylees, S. E.: On the selective inhibition of serotonin uptakein vivo by Org 6582. Europ. J. Pharmacol.40, 121–130 (1976).
Svensson, T. H., Usdin, T.: Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants: alpha-receptor mediation. Science202, 1089–1091 (1978).
Tang, S. W., Helmeste, D. M., Stancer, H. C.: Interaction of antidepressants with clonidine on rat brain total 3-methosy-4-hydroxyphenylglycol. Can. J. Physiol. Pharmacol.57, 435–437 (1979).
U'Prichard, D. C., Bechtel, W. D., Rouot, B. M., Snyder, S. H.: Multiple apparentalpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine. Mol. Pharmacol.16, 47–60 (1979).
Vetulani, J., Sulser, F.: Action of various antidepressant treatments reduces reactivity of noradrenergic cyclic AMP-generating system in limbic forebrain. Nature257, 495–496 (1975).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sugrue, M.F. Some effects of chronic antidepressant treatments on rat brain monoaminergic systems. J. Neural Transmission 57, 281–295 (1983). https://doi.org/10.1007/BF01248999
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01248999