Abstract
Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor with therapeutic benefit in patients with obsessive-compulsive disorder (OCD). To evaluate the effect of chronic FLX treatment on 5-HT1A receptor responsivity, hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT1A receptor ligand ipsapirone (IPS) were examined in patients with primary OCD. A single dose of 0.3 mg/kg of IPS or placebo were given under double-blind, random-assignment conditions to ten patients before and during FLX treatment. The ability of IPS to induce hypothermia and ACTH/cortisol release was significantly attenuated during chronic FLX as compared to the pretreatment IPS challenge. The behavioral effects of IPS, though minimal, were less pronounced during FLX treatment. While FLX was effective in reducing the severity of OC symptoms, no significant correlation between attenuation of 5-HT1A receptor-mediated functional measures and FLX-induced improvement in OC symptoms was detected. These findings are consistent with the development of adaptive hyporesponsivity of the 5-HT1A receptor-effector system complex possibly involving subsensitivity of the 5-HT1A receptor itself and/or decreased functional activity of the postreceptor signal transduction. Modulation of 5-HT1A receptor-effector system function may be critical to the antidepressant/anti-OC efficacy of 5-HT reuptake inhibitors.
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References
Anderson IM, Cowen PJ, Grahame-Smith DG (1990) Neuroendocrine and temperature effects of gepirone in humans. Psychopharmacology 100:498–503
Aulakh CS, Wozniak KM, Hill JL, Murphy DL (1988) Differential effects of long-term antidepressant treatments on 8-OH-DPAT-induced increases in plasma prolactin and corticosterone in rats. Eur J Pharmacol 156:395–400
Birnbaumer L (1990) G proteins in signal transduction. Annu Rev Pharmacol Toxicol 30:675–705
Blier P, de Montigny C, Chaput Y (1988) Electrophysiological assessment of the effects of antidepressant treatments on the efficacy of 5-HT neurotransmission. Clin Neuropharmacol 11:1S-10S
Chaput Y, de Montigny C, Tardif (1986) Effects of a selective 5HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: electrophysiological studies in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 333:342–348
Coccaro EF, Gabriel S, Mahon T, Macaluso J, Siever LJ (1990) Preliminary evidence of a 5-HT1-like component of the prolactin response to buspirone hydrochloride in man. Arch Gen Psychiatry 47:594–595
Cowen PJ (1987) Psychotropic drugs and human 5-HT neuroendocrinology. TIPS 8:105–108
Cowen PJ, Anderson IM, Grahame-Smith DG (1990) Neuroendocrine effects of azapirones. J Clin Psychopharmacol 10:21S-25S
Frazer A, Hensler JG (1991) 5HT1A receptors and 5-HT1A-mediated responses: effect of treatments that modify serotonergic neurotransmission. Ann NY Acad Sci 600:460–475
Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS (1989) The Yale-Brown obsessive compulsive scale: I. Development, use, and reliability. Arch Gen Psychiatry 46:1006–1011
Goodwin GM, De Souza RJ, Green AR (1987) Attenuation by electroconvulsive shock and antidepressant drugs of the 5-HT1A receptor-mediated hypothermia and serotonin syndrome produced by 8-OH-DPAT in the rat. Psychopharmacology 91:500–505
Grahame-Smith DG (1989) Neuropharmacological adaptive effects in the action of antidepressant drugs, ECT and lithium. In: Briley M, Fillion G (eds) New concepts in depression. Pierre Fabre Monograph Series, vol 2. Macmillan, Cambridge, pp 1–14
Gudelsky GA, Koenig JI, Jackman H, Meltzer HY (1986) Suppression of the hypo- and hyperthermic responses to 5-HT agonists following repeated administration of monoamine oxidase inhibitors. Psychopharmacology 90:403–407
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Hartig PR (1989) Molecular biology of 5-HT receptors. TIPS 10:64–69
Hensler JG, Kovachich GB, Frazer A (1991) A quantitative autoradiography study of serotonin1A receptor regulation: effect of 5,7-dihydroxytryptamine and antidepressant treatments. Neuropsychopharmacology 4:131–144
Lesch KP, Poten B, Söhnle K, Schulte HM (1990a) Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans. Eur J Clin Pharmacol 39:17–19
Lesch KP, Söhnle K, Poten B, Rupprecht R, Schöllnhammer G, Schulte HM (1990b) Corticotropin and cortisol secretion following central 5-hydroxytryptamine-1A (5-HT1A) receptor activation: effects of 5-HT receptor and β-adrenoceptor antagonists. J Clin Endocrinol Metab 70:670–674
Lesch KP, Mayer S, Disselkamp-Tietze J, Hoh A, Wiesmann M, Osterheider M, Schulte HM (1990c) 5-HT1A receptor responsivity in unipolar depression: evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls. Biol Psychiatry 28:620–628
Lesch KP, Hoh A, Disselkamp-Tietze J, Wiesmann M, Osterheider M, Schulte HM (1991a) 5-Hydroxytryptamine1A (5-HT1A) receptor responsivity in obsessive-compulsive disorder: comparison of patients and controls. Arch Gen Psychiatry 48:540–547
Lesch KP, Aulakh CS, Tolliver TJ, Murphy DL (1991b) Gi protein in rat brain: effects of long-term antibipolar and antidepressant treatment. Biol Psychiatry 29:116A
Meltzer HY, Gudelsky GA, Lowy MT, Nash JF, Koenig JI (1991) Neuroendocrine effects of buspirone: mediation by dopaminergic and serotonergic mechanisms. In: Tunnicliff G, Eison AS, Taylor DP (eds) Buspirone: mechanisms and clinical effects. Academic Press, New York, pp 177–192
Murphy DL, Pato MT, Pigott TA (1990a) Obsessive-compulsive disorder: treatment with serotonin-selective uptake inhibitors, azapirones, and other agents. J Clin Psychopharmacol 10:91S-100S
Murphy DL, Lesch KP, Pigott TA (1990b) Potential relevance of the partial agonist properties of different serotonergic agents studied in humans to their neuropharmacologic effect. Abstracts of the ACNP 1990 Annual Meeting, p 80
Newman ME, Lerer B (1988) Chronic electroconvulsive shock and desipramine reduce the degree of inhibition by 5-HT and carbachol of forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Eur J Pharmacol 148:257–264
Newman M, Lerer B (1990) 5-HT1A receptor-mediated effects of antidepressants: relation to G protein function. Clin Neuropharmacol 13:237S-238S
Newman ME, Drummer D, Lerer B (1990) Single and combined effects of desipramine and lithium on serotonergic receptor number and second messenger function in rat brain. J Pharmacol Exp Ther 252:826–831
Rausch JL, Stahl SM, Hauger RL (1990) Cortisol and growth hormone responses to the 5-HT1A agonist gepirone in depressed patients. Biol Psychiatry 28:73–78
Traber J, Glaser T (1987) 5-HT1A receptor-related anxiolytics. TIPS 8:432–437
Wozniak KM, Aulakh CS, Hill JL, Murphy DL (1988) The effect of 8-OH-DPAT on temperature in the rat and its modification by chronic antidepressant treatments. Pharmacol Biochem Behav 30:451–456
Zohar J, Insel TR, Zohar-Kadouch RC, Hill JL, Murphy DL (1988) Serotonergic responsivity in obsessive-compulsive disorder: effect of chronic clomipramine treatment. Arch Gen Psychiatry 45:167–172
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Part of this work was presented at the 17th Congress of the CINP, Kyoto, Japan, September 10–14, 1990
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Lesch, K.P., Hoh, A., Schulte, H.M. et al. Long-term fluoxetine treatment decreases 5-HT1A receptor responsivity in obsessive-compulsive disorder. Psychopharmacology 105, 415–420 (1991). https://doi.org/10.1007/BF02244438
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DOI: https://doi.org/10.1007/BF02244438