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Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor, citalopram

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Abstract

The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. Administration of citalopram in the diet at a daily dose of 99 μmol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 μmol/kg for 13 days and after oral bolus injection (49 μmol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.

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References

  • Anderson JL (1983) Serotonin receptor changes after chronic antidepressant treatments: Ligand binding, electrophysiological, and behavioral studies. Life Sci 32:1791–1801

    Google Scholar 

  • Anggård E, Gunne L-M, Niklasson F (1970) Gas chromatographic determination of amphetamine in blood, tissue, and urine. Scand J Clin Lab Invest 26:137–144

    Google Scholar 

  • Antelman SM, Chiodo LA (1981) Dopamine autoreceptor subsensitivity: A mechanism common to the treatment of depression and the induction of amphetamine psychosis? Biol Psychiatry 16:717–727

    Google Scholar 

  • Arnt J, Bøgesø KP, Christensen AV, Hyttel J, Larsen J-J, Svendsen O (1983) Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers. Psychopharmacology 81:199–207

    Google Scholar 

  • Arnt J, Hyttel J, Fredricson Overø K (1984) Prolonged treatment with the specific 5-HT-uptake inhibitor citalopram: Effect on dopaminergic and serotonergic functions. Pol J Pharmacol Pharm 36:221–230

    Google Scholar 

  • Blier P, De Montigny C (1983) Electrophysiological investigations on the effect of repeated zimelidine administration on serotonergic neurotransmission in the rat. J Neurosci 3:1270–1278

    Google Scholar 

  • De Montigny C, Aghajanian GK (1978) Tricyclic antidepressants: Long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science 202:1303–1306

    Google Scholar 

  • Fredricson Overø K (1981) Fluorescence assay of citalopram and its metabolites in plasma by scanning densitometry of thin-layer chromatograms. J Chromatogr 224:526–531

    Google Scholar 

  • Fredricson Overø K (1982a) Kinetics of citalopram in test animals; drug exposure in safety studies. Prog Neuro-Psychopharmacol Biol Psychiatry 6:297–309

    Google Scholar 

  • Fredricson Overø K (1982b) Kinetics of citalopram in man; plasma levels in patients. Prog Neuro-Psychopharmacol Biol Psychiatry 6:311–318

    Google Scholar 

  • Friedman E, Dallob A (1979) Enhanced serotonin receptor activity after chronic treatment with imipramine or amitriptyline. Commun Psychopharmacol 3:89–92

    Google Scholar 

  • Friedman E, Cooper TB, Dallob A (1983) Effects of chronic antidepressant treatment on serotonin receptor activity in mice. Eur J Pharmacol 89:69–76

    Google Scholar 

  • Fuxe K, Ogren S-O, Agnati LF, Benfenati F, Fredholm B, Andersson K, Zini I, Eneroth P (1983) Chronic antidepressant treatment and central 5-HT synapses. Neuropharmacology 22:389–400

    Google Scholar 

  • Green AR, Hall JE, Rees AR (1981) A behavioural and biochemical study in rats of 5-hydroxytryptamine receptor agonists and antagonists, with observations on structure-activity requirements for the agonists. Br J Pharmacol 73:703–719

    Google Scholar 

  • Hjorth S, Carlsson A, Clark D, Svensson K, Wikström H, Sanchez D, Lindberg P, Hacksell U, Arvidsson L-E, Johansson A, Nilsson JLG (1983) Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP. Psychopharmacology 81:89–99

    Google Scholar 

  • Horn AS, Philipson OT (1976) A noradrenaline sensitive adenylate cyclase in the rat limbic forebrain: Preparations, properties and the effects of agonists, adrenolytics and neuroleptic drugs. Eur J Pharmacol 37:1–11

    Google Scholar 

  • Hwang EC, Van Woeft MH (1980) Acute versus chronic effects of serotonin uptake blockers on potentiation of the “serotonin syndrome”. Commun Psychopharmacol 4:161–167

    Google Scholar 

  • Hyttel J (1982) Citalopram — pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuro-Psychopharmacol Biol Psychiatry 6:277–295

    Google Scholar 

  • Hyttel J, Fredricson Overø K, Arnt J (1984) Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor, citalopram. Psychopharmacology 83:20–27

    Google Scholar 

  • Kopanski C, Türck M, Schultz JE (1983) Effects of long-term treatment of rats with antidepressants on adrenergic-receptor sensitivity in cerebral cortex structure activity. Neurochem Int 5:649–659

    Google Scholar 

  • Kragh-Sørensen P (1983) A controlled, double-blind multicentre trial comparing clomipramine and a new, highly selective 5-HT-uptake-inhibitor, citalopram (Lu 10-171). Abstract. VII World Congress in Psychiatry, Vienna, July 11–16, p 482

  • Lucki I, Frazer A (1982) Prevention of the serotonin syndrome in rats by repeated administration of monoamine oxidase inhibitors but not tricyclic antidepressants. Psychopharmacology 77:205–211

    Google Scholar 

  • Maj J, Rogóz Z, Skuza G, Sowińska H (1982) Effects of chronic treatment with antidepressants on aggressiveness induced by clonidine in mice. J neural Transm 55:19–25

    Google Scholar 

  • Mertens C (1983) A controlled double-blind clinical trial with a new highly selective 5-HT-re-uptake inhibitor, citalopram (Lu 10–171) versus mianserin in depressed patients. Abstract. VII World Congress in Psychiatry, Vienna, July 11–16, p 441

  • Mogilnicka E, Klimek V (1979) Mianserin, danitracen and amitriptyline withdrawal increases the behavioural responses of rats to 1-5-HTP. J Pharm Pharmacol 31:704–705

    Google Scholar 

  • Ogren S-O, Fuxe K, Archer T, Johansson G, Holm AC (1982) Behavioural and biochemical studies on the effects of acute and chronic administration of antidepressant drugs on central serotonergic receptor mechanisms. In: Langer SZ, Takahashi R, Segawa T, Briley M (eds) New vistas in depression. Advances in the Biosciences 40: 11–19

  • Olpe H-R (1981) Differential effects of clomipramine and clorgyline on the sensitivity of cortical neurons to serotonin: Effect of chronic treatment. Eur J Pharmacol 69:375–377

    Google Scholar 

  • Olpe H-R, Schellenberg A (1980) Reduced sensitivity of neurons to noradrenaline after chronic treatment with antidepressant drugs. Eur J Pharmacol 63:7–13

    Google Scholar 

  • Ortmann R, Waldmeier PC, Radeke E, Felner A, Delini-Stula A (1980) The effects of 5-HT uptake- and MAO-inhibitors on 1-5-HTP-induced excitation in rats. Naunyn-Schmiedeberg's Arch Pharmacol 311:185–192

    Google Scholar 

  • Pawlowski L, Stach R, Kacz D (1982) Chronic treatment with amitriptyline and zimelidine: Attenuation of serotonin-induced changes in the light-evoked responses from the occipital cortex. In: Langer SZ, Takahashi R, Segawa T, Briley M (eds) New vistas in depression. Advances in the Biosciences 40: 73–80

  • Peroutka S-J, Lebowitz RM, Snyder SH (1981) Two distinct central serotonin receptors with different physiological functions. Science 212:827–829

    Google Scholar 

  • Randrup A, Munkvad I, Fog R, Gerlach J, Molander L, Kjellberg B, Scheel-Krüger J (1975) Mania, depression, and brain dopamine. Curr Dev Psychopharmacol 2:206–247

    Google Scholar 

  • Rolinski Z, Scheel-Krüger J (1973) The effect of dopamine and noradrenaline antagonists on amphetamine induced locomotor activity in mice and rats. Acta Pharmacol Toxicol 33:385–399

    Google Scholar 

  • Serra G, Argiolas A, Klimek V, Fadda F, Gessa GL (1979) Chronic treatment with antidepressants prevents the inhibitory effect of small doses of apomorphine on dopamine synthesis and motor activity. Life Sci 25:415–424

    Google Scholar 

  • Serra G, Argiolas A, Fadda F, Melis MR, Gessa GL (1981) Repeated electroconvulsive shock prevents the sedative effect of small doses of apomorphine. Psychopharmacology 73:194–196

    Google Scholar 

  • Siegel S (1956) Non-parametric statistics for the behavioural sciences. McGraw-Hill Inc., New York

    Google Scholar 

  • Snyder SH, Peroutka SJ (1982) A possible role of serotonin receptors in antidepressant drug action. Pharmacopsychiatr 15:131–134

    Google Scholar 

  • Spyraki C, Fibiger HC (1981) Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine. Eur J Pharmacol 74:195–206

    Google Scholar 

  • Stoltz JF, Marsden CA, Middlemiss DN (1983) 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

    Google Scholar 

  • Sulser F, Mishra R (1982) Regulation of central noradrenergic receptor function and its relevance to the therapy of depression. In: Langer SZ, Takahashi R, Segawa T, Briley M (eds) New vistas in depression. Advances in the Biosciences 40: 37–47

  • Van der Waerden BL, Nievergelt E (1956) Tables for comparing two samples by X-test and sign test. Springer Verlag, Berlin

    Google Scholar 

  • Welch J, Kim H, Fallon S, Liebman J (1982) Do antidepressants induce dopamine autoreceptor subsensitivity? Nature 298:301–302

    Google Scholar 

  • Wielosz M (1981) Increased sensitivity to dopaminergic agonists after repeated electroconvulsive shock (ECS) in rats. Neuropharmacology 20:941–945

    Google Scholar 

  • Willner P (1983) Dopamine and depression: A review of recent evidence III. The effects of antidepressant treatments. Brain Res Rev 6:237–246

    Google Scholar 

  • Yuwiler A, Plotkin S, Geller E, Ritvo ER (1970) A rapid accurate procedure for the determination of serotonin in whole human blood. Biochem Med 3:426–431

    Google Scholar 

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Authors and Affiliations

  1. The Research Laboratories, H. Lundbeck A/S, Ottiliavej 7-9, DK-2500, Copenhagen-Valby

    Jørn Arnt, Kerstin Fredricson Overø & John Hyttel

  2. Department of Clinical Chemistry, Sct. Hans Mental Hospital, DK-4000, Roskilde, Denmark

    Ruth Olsen

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  1. Jørn Arnt
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  2. Kerstin Fredricson Overø
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  3. John Hyttel
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  4. Ruth Olsen
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Arnt, J., Fredricson Overø, K., Hyttel, J. et al. Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor, citalopram. Psychopharmacology 84, 457–465 (1984). https://doi.org/10.1007/BF00431450

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