Abstract
Changes in [3H]-5HT and [3H]-spiperone binding in vitro and ex vivo following withdrawal from chronic administration of certain antidepressants and the 5HT antagonist metergoline were compared with changes in 5-methoxy-N′,N′-dimethyltryptamine (5MEODMT, 2.5 mg/kg) induced behaviour following acute, chronic and withdrawal from chronic treatment with the same drugs. In vitro metergoline, amitriptyline, imipramine and chlorimipramine displaced [3H]-5HT and [3H]-spiperone binding in that order of potency. Iprindole weakly blocked only [3H]-spiperone binding while fluoxetine had no effect on either ligand at concentrations up to 100 μm. Following 72h withdrawal from 14 days chronic treatment ex vivo [3H]-5HT binding was unaffected by any of the drugs, while fluoxetine (15 mg/kg), chlorimipramine (15 mg/kg) and iprindole (15 mg/kg) significantly reduced [3H]-spiperone binding. The 5MEODMT behavioural response was attenuated by metergoline (2 mg/kg) and amitriptyline (15 mg/kg) (Stolz and Marsden 1982) and by iprindole (15 mg/kg) and imipramine (15 mg/kg). Neither fluoxetine (2 mg/kg) nor chlorimiprmaine (15 mg/kg) altered the behavioural response. After 14 days chronic treatment metergoline, amitriptyline, chlorimipramine, fluoxetine and imipramine significantly reduced the 5MEODMT response while the reduction with iprindole did not reach significance. When further tested after 72h withdrawal from chronic treatment fluoxetine-and chlorimipramine-treated rats showed a significantly reduced response, imipramine-treated rats an increased response, while those given iprindole showed no significant change. The results suggest that decreased functional responsiveness observed following treatment with 5HT uptake blockers corresponds with changes in [3H]-spiperone but not [3H]-5HT binding. In contrast the enhanced functional response on withdrawal from metergoline, amitriptyline (Stolz and Marsden 1982) or imipramine does not correlate with changes in the binding of either ligand.
Similar content being viewed by others
References
Bannerjee SP, Kung LS, Riggi SJ, Chanda SK (1977) Development of β-adrenergic receptor subsensitivity by antidepressants. Nature 268:455–456
Baumann PA, Maitre L (1977) Blockade of presynaptic alpha-receptors and of amine uptake in the rat brain by the antidepressant mianserin. Naunyn-Schmiedeberg's Arch Pharmacol 300:31–37
Braithwaite RA (1974) Steady state plasma concentrations during single and multiple dosage schedules of amitriptyline. Psychol Med 4: 338–341
Buus Lassen J (1972) Potentiation of anticonvulsant effects of 5-hydroxytryptamine in mice by tricyclic antidepressants and monoamine oxidase inhibitors. 5th Int Congr Pharmacol 7:23–28
Buxton DA, Marsden CA, Stolz JF (1981) Withdrawal from chronic treatment with 5-hydroxytryptamine antagonists enhances the behavioural response to 5-methoxy-N′,N′-dimethyltryptamine. Br J Pharmacol 74:215P
de Montigny C, Aghajania GK (1978) Tricyclic antidepressants: Long term treatment increases the responsivity of rat forebrain neurones to serotonin. Science 202:1303–1306
Evans JPM, Grahame-Smith DG, Green AR, Tordoff AFC (1976) Electroconvulsive shock increases the behavioural responses of rats to brain 5-hydroxytryptamine accumulation and central nervous system stimulant drugs. Br J Pharmacol 56:193–200
Fillion G, Fillion MP (1981) Modulation of affinity of postsynaptic serotonin receptors by antidepressant drugs. Nature 292:349–351
Friedman E, Dallob A (1981) Enhanced serotonin receptor activity after chronic treatment with imipramine and amitriptyline. Commun Psychopharmacol 3:89–92
Fuxe K, Agnati L, Everitt B (1975) Effects of metergoline on central monoamine neurones. Evidence for a blockade of 5HT receptors. Neurosci Lett 1:283–290
Fuxe K, Ögren S-O, Agnati L, Gustafsson JA, Jonsson G (1977) On the mechanism of action of the antidepressant drug amitriptyline and nortriptyline. Evidence for 5-hydroxytryptamine receptor blocking activity. Neurosci Lett 6:339–343
Horn AS, Trace RCAM (1974) Structure activity relationships for the inhibition of 5-hydroxytryptamine uptake by tricyclic antidepressants into synptosomes from serotonin neurones in rat brain homogenates. Br J Pharmacol 51:399–403
Hwang EC, Van Voert MH (1980) Acute versus chronic effects of serotonin uptake blockers on potentiation of the ‘serotonin syndrome’. Comm Psychopharmacol 4:161–167
Jones RSG (1980) 5-hydroxytryptamine induced behavioural effects following chronic administration of antidepressant drugs. Psychopharmacology 65:307–311
Kellar KJ, Cascio CS, Butler JA, Kurtzke RN (1981) Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain. Eur J Pharmacol 69:515–518
Maggi A, U'Prichard DC, Enna SJ (1980) Differential effects of antidepressant treatment on brain monoaminergic receptors. Eur J Pharmacol 61:91–98
Maj J, Lewandowska A, Rawtow A (1979) Central antiserotonin action of amitriptyline. Pharmakopsychiat Neuropsychopharmakol 12:281–285
Middlemiss DN, Carroll JA, Fisher RW, Mounsey IJ (1980) Does [3H]-spiperone label a 5-hydroxytryptamine receptor in the frontal cortex of the rat? Eur J Pharmacol 66:253–254
Middlemiss DN (1982) Multiple 5-hydroxytryptamine receptors in the central nervous system. In: De Belleroche J (ed) Presynaptic receptors. Ellis Horwood, Chichester, pp 46–74
Ögren SO, Fuxe V, Agnati LF, Gustafsson JA, Jonsson G, Holm AC (1979) Reevaluation of the indolamine hypothesis of depression. Evidence for a reduction in functional activity of central 5HT systems by antidepressant drugs. J Neural Transm 46:85–103
Olpe HR, Schellenberg A (1981) The sensitivity of corticol neurones to serotonin: effect of chronic treatment with antidepressants serotonin-uptake inhibitors and monoamine-oxidase blocking durgs. J Neural Transm 51:233–244
Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors. Differential binding of [3H]-5-hydroxytryptamine [3H]-lysergic acid diethylamide and [3H]-spiperone. Mol Pharmacol 16:687–699
Peroutka SJ, Lebovitz RM, Snyder SH (1981) Two distinct central serotonin receptors with different physiological functions. Science 212:827–829
Rogers HJ, Morrison PJ, Bradbrook ID (1978) The half life of amitriptyline. Br J Clin Pharmacol 6:181–183
Samanin R, Mennini T, Ferraris A, Bendotti C, Borsini F (1980) Repeated treatment with d-fenfluramine or metergoline alters cortex, binding and serotonergic sensitivity in rats. Eur J Pharmacol 61:203–206
Stolz JF, Marsden CA (1981) Behavioural effects of long term inhibition of 5-hydroxytryptamine receptors using metergoline. J Physiol (Paris) 77:385–388
Stolz JF, Marsden CA (1982) Withdrawal from chronic treatment with metergoline dl-propranolol and amitriptyline enhances serotonin receptor mediated behaviour in the rat. Eur J Pharmacol 79:17–22
Tang SW, Seeman P (1980) Effect of antidepressant drugs on serotonergic and adrenergic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 311:255–261
Vetulani J, Lebrecht U, Pilc A (1981) Enhancement of responsiveness of the central serotonin system and serotonin-2 receptor density in rat frontal cortex by electroconvulsive treatment. Eur J Pharmacol 76:81–85
Wirz-Justice A, Krauchi K, Lichtsteiner M, Feer H (1978) Is it possible to modify serotonin receptor sensitivity? Life Sci 23:1249–1254
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stolz, J.F., Marsden, C.A. & Middlemiss, D.N. Effect of chronic antidepressant treatment and subsequent withdrawal on [3H]-5-hydroxytryptamine and [3H]-spiperone binding in rat frontal cortex and serotonin receptor mediated behaviour. Psychopharmacology 80, 150–155 (1983). https://doi.org/10.1007/BF00427959
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00427959