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Fluoxetine, a Highly Selective Serotonin Reuptake Inhibitor: A Review of Preclinical Studies

Published online by Cambridge University Press:  06 August 2018

Michael J. Schmidt ,
Ray W. Fuller  and
David T. Wong
Michael J. Schmidt
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Ray W. Fuller
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
David T. Wong
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
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Extract

The chemical structure of fluoxetine, (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine, as shown in Fig. 1, lacks the three-fused ring system contained in tricyclic antidepressant drugs (TCAs) such as imipramine and amitriptyline. The p-trifluoromethyl substituent on the phenoxy ring of fluoxetine is an important determinant of its potency and its specificity as a serotonin-uptake inhibitor, e.g. the analogue having an o-trifluoromethyl substituent on that ring is only about one-hundredth as potent as fluoxetine in inhibiting serotonin uptake (Wong et al, 1975a). Nisoxetine (Wong et al, 1975b) and tomoxetine (Wong et al, 1982) are analogues differing from fluoxetine only in having an o-methoxy or an o-methyl substituent respectively, in place of the p-trifluoromethyl substituent on the phenoxy ring. Nisoxetine (LY94939) and tomoxetine (LY 139603) are potent and highly selective inhibitors of norepinephrine uptake (Wong et al, 1975b, 1982), differing strikingly from fluoxetine in specificity of uptake inhibition.

Fluoxetine has been shown to be a potent and selective inhibitor of serotonin uptake in laboratory animals; it is orally effective and has a long duration of action. This compound has been a valuable pharmacological tool to study the mechanisms of serotonergic neurotransmission and physiological functions of brain serotonin neurons (Fuller & Wong, 1977; Wong et al, 1985a; Fuller & Wong, 1987). The present paper summarises some of the pre-clinical studies which have characterised fluoxetine as a selective inhibitor of serotonin uptake.

Type
Research Article
Information
The British Journal of Psychiatry , Volume 153 , Issue S3: Progress in Antidepressant Therapy , September 1988 , pp. 40 - 46
Copyright
Copyright © 1988 The Royal College of Psychiatrists 

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References

Berzsenyi, P., Galateo, E. & Valzelli, L. (1983) Fluoxetine activity on muricidal aggression induced in rats by p-chloro-phenylalanine. Aggressive Behavior, 9, 333–338.Google Scholar
Bymaster, F. P. & Wong, D. T. (1977) Effect of Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine, on synthesis of 3H-serotonin from 3H-tryptophan in rat brain. The Pharmacologist, 16, 244.Google Scholar
Dumbrille-Ross, A. & Tang, S. W. (1983) Manipulations of synaptic serotonin: discrepancy of effects on serotonin S1 and S2 sites. Life Sciences, 32, 2677–2684.CrossRefGoogle ScholarPubMed
Feighner, J. P. & Cohn, J. B. (1985) Double-blind comparative trials of fluoxetine and doxepin in geriatric patients with major depressive disorder. Journal of Clinical Psychiatry, 46, 20–25.Google Scholar
Frazer, A., Pandey, G., Mendels, J., Neeley, S., Kane, M. & Hess, M. E. (1974) The effect of tri-iodothyronine in combination with imipramine in [3H] -cyclic AMP production in slices of rat cerebral cortex. Neuropharmacology, 13, 1131–1140.Google Scholar
Fuller, R. W. (1980) Mechanism by which uptake inhibitors antagonise p-chloroamphetamine-induced depletion of brain serotonin. Neurochemical Research, 5, 241–245.Google Scholar
Fuller, R. W. & Snoddy, H. D. (1980) Effect of serotonin-releasing drugs on serum corticosterone concentration in rats. Neuroendocrinology, 31, 96–100.CrossRefGoogle ScholarPubMed
Fuller, R. W. & Wong, D. T. (1977) Inhibition of serotonin reuptake. Federation Proceedings, 36, 2154–2158.Google Scholar
Fuller, R. W. & Wong, D. T. (1987) Serotonin re-uptake blockers in vitro and in vivo. Journal of Clinical Psychopharmacology, 7, 365–435.Google Scholar
Fuller, R. W., Perry, K. W. & Molloy, B. B. (1974a) Effect of an uptake inhibitor on serotonin metabolism in rat brain: studies with 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140). Life Sciences, 15, 1161–1171.CrossRefGoogle Scholar
Fuller, R. W., Snoddy, H. D. & Molloy, B. B. (1974b) Comparison of the specificity of 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine and chlorimipramine as amine uptake inhibitors in mice. European Journal of Pharmacology, 28, 233–236.CrossRefGoogle ScholarPubMed
Fuller, R. W., Snoddy, H. D. & Molloy, B. B. (1975) Effect of 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine on the depletion of brain serotonin by 4-chloroamphetamine. Journal of Pharmacology and Experimental Therapeutics, 193, 796–803.Google Scholar
Fuller, R. W., Snoddy, H. D. & Molloy, B. B. (1976) Pharmacologic evidence for a serotonin in neural pathway involved in hypothalamus-pituitary-adrenal function in rats. Life Sciences, 19, 337–346.Google Scholar
Fuller, R. W., Snoddy, H. D., Perry, K. W., Bymaster, F. P. & Wong, D. T. (1977) Importance of duration of drug action in the antagonism of p-chloroamphetamine depletion of brain serotonin - comparison of fluoxetine and chlorimipramine. Biochemical Pharmacology, 29, 193–198.Google Scholar
Geyer, M. A., Dawsey, W. J. & Mandell, A. J. (1978) Fading: a new cytofluorimetric measure quantifying serotonin in the presence of catecholamines at the cellular level in brain. Journal of Pharmacology and Experimental Therapeutics, 207, 650–667.Google Scholar
Gibbs, D. M. & Vale, W. (1983) Effect of the serotonin reuptake inhibitor fluoxetine on corticotropin-releasing factor and vasopressin secretion into hypophyscal portal blood. Brain Research, 280, 176–179.Google Scholar
Goldman, L. S., Alexander, R. C. & Luchins, D. J. (1986) Monoamine oxidase inhibitors and tricyclic antidepressants: comparison of their cardiovascular effects. Journal of Clinical Psychiatry, 47, 225–229.Google Scholar
Guan, X.-M. & McBride, W. J. (1986) Selective action of fluoxetine on the extracellular pool of serotonin in the nucleus accumbens. Society for Neuroscience Abstracts, 12, 428.Google Scholar
Harvey, J. A., McMaster, S. E. & Fuller, R. W. (1977) Comparison between the neurotoxic and serotonin-depleting effects of various halogenated derivatives of amphetamine in the rat. Journal of Pharmacology and Experimental Therapeutics, 202, 581–589.Google ScholarPubMed
Horng, J. S. & Wong, D. T. (1976) Effects of serotonin uptake inhibitor, Lilly 110140, on transport of serotonin in rat and human blood platelets. Biochemical Pharmacology, 25, 865–867.Google Scholar
Hyttel, J. (1982) Citalopram-pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 6, 277–295.Google Scholar
Hyttel, J. & Larsen, J.-J. (1985) Serotonin-selective antidepressants. Acta Pharmacologica et Toxicologica, 56, 146–153.Google Scholar
Klimek, V. & Nielsen, M. (1987) Chronic treatment with antidepressants decreases the number of [3H]SCH23390 binding sites in the rat striatum and limbic system. European Journal of Pharmacology, 139, 163–169.CrossRefGoogle ScholarPubMed
Lemberger, L., Rowe, H., Carmichael, R., Crabtree, R., Horng, J. S., Bymaster, F. & Wong, D. (1978) Fluoxetine, a selective serotonin uptake inhibitor. Clinical Pharmacology and Therapeutics, 23, 421–429.Google Scholar
Maj, J., Rogoz, Z., Skuza, G. & Sowinska, H. (1983) The effect of selective inhibitors of noradrenaline and serotonin uptake on reserpine and apomorphine induced hypothermia in mice. Polish Journal of Pharmacology and Pharmacy, 35, 49–57.Google Scholar
Marsden, C. A., Conti, J., Strope, E., Curzon, G. & Adams, R. N. (1979) Monitoring 5-hydroxytryptamine release in the brain of the freely moving unanaesthetized rat using in vivo voltammetry. Brain Research, 171, 85–99.Google Scholar
Meek, J. L., Fuxe, K. & Carlsson, A. (1971) Blockade of p-chloroamphetamine induced 5-hydroxytryptamine depletion by chlorimipramine, chlorpheniramine and meperidine. Biochemical Pharmacology, 20, 707–709.Google Scholar
Mishra, R., Leith, N. J., Steranka, L. & Sulser, F. (1981) The noradrenaline receptor coupled adenylate cyclase system in brain. Lack of modification by changes in the availability of serotonin. Naunyn-Schmiedeberg's Archives of Pharmacology, 316, 218–224.Google Scholar
Molina, V. A., Gobaille, S. & Mandel, P. (1986) Effects of serotonin-mimetic drugs on mouse-killing behavior. Aggressive Behavior, 12, 201–211.3.0.CO;2-5>CrossRefGoogle Scholar
Molina, V. A., Ciesielski, L., Gobaille, S., Isel, F. & Mandel, P. (1987) Inhibition of mouse killing behavior by serotonin-mimetic drugs: Effects of partial alterations of serotonin neurotransmission. Pharmacology Biochemistry & Behavior, 27, 123–131.Google Scholar
Montgomery, S. A. (1982) The nonselective effect of selective antidepressants. In Typical and Atypical Antidepressants: Clinical Practice (eds Costa, E. & Racagni, G.). New York: Raven Press.Google Scholar
Mortensen, S. A. (1984) Cyclic antidepressants and cardiotoxicity. The Practitioner, 228, 1180–1183.Google Scholar
Peroutka, S. J. & Snyder, S. H. (1980) Long-term antidepressant treatment decreases spiroperidol-labelled serotonin receptor binding. Science, 210, 88–90.Google Scholar
Porsolt, R. D., Bertin, A., Blavet, N., Deniel, M. & Jalfre, M. (1979) Immobility induced by forced swimming in rats: Effects of agents which modify central catecholamine and serotonin activity. European Journal of Pharmacology, 57, 201–210.Google Scholar
Rehavi, M., Ramot, O., Yavetz, B. & Sokolovsky, M. (1980) Amitriptyline: long-term treatment elevates a-adrenergic and muscarinic receptor binding in mouse brain. Brain Research, 194, 443–453.Google Scholar
Richelson, E. & Nelson, A. (1984) Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. Journal of Pharmacology and Experimental Therapeutics, 230, 94–102.Google Scholar
Ross, S. B. & Renyi, A. L. (1975) Tricyclic antidepressant agents. II. Effect of oral administration on the uptake of 3H-noradrenaline and 14C-5-hydroxytryptamine in slices of the midbrain-hypothalamus region of the rat. Acta Pharmacologica et Toxicologica, 36, 395–408.Google Scholar
Ross, S. B. & Renyi, A. L. (1977) Inhibition of the neuronal uptake of 5-hydroxytryptamine and noradrenaline in rat brain by (Z)- and (E)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)-allylamines and their secondary analogues. Neuropharmacology, 16, 57–63.Google Scholar
Ross, S. B., Hall, H., Renyi, A. L. & Westerlund, D. (1981) Effects of zimelidine on serotoninergic and noradrenergic neurons after repeated administration in the rat. Psychopharmacology, 72, 219–225.Google Scholar
Schmidt, M. J. & Thornberry, J. F. (1977) Norepinephrine-stimulated cyclic AMP accumulation in brain slices in vitro after serotonin depletion or chronic administration of selective amine reuptake inhibitors. Archives Internationales de Pharmacodynamie et de Therapie, 229, 42–51.Google Scholar
Segawa, T., Mizuta, T. & Nomura, Y. (1979) Modifications of central 5-hydroxytryptamine binding sites in synaptic membranes from rat brain after long-term administration of tricyclic antidepressants. European Journal of Pharmacology, 58, 75–83.Google Scholar
Slater, I. H., Rathbun, R. C. & Kattau, R. (1979) Role of 5-hydroxytryptaminergic and adrenergic mechanism in antagonism of reserpine-induced hypothermia in mice. Journal of Pharmacy and Pharmacology, 31, 108–110.Google Scholar
Smith, C. B., Garcia-Sevilla, J. A. & Hollingsworth, P. J. (1981) a2-Adrenoreceptors in rat brain are decreased after long-term tricyclic antidepressant drug treatment. Brain Research, 210, 413–418.CrossRefGoogle Scholar
Stark, P. & Hardison, C. D. (1985) A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder. Journal of Clinical Psychiatry, 46, 53–58.Google Scholar
Stark, P., Fuller, R. W. & Wong, D. T. (1985) The pharmacologic profile of fluoxetine. Journal of Clinical Psychiatry, 46, 7–13.Google Scholar
Steinberg, M. I., Smallwood, J. K., Holland, D. R., Bymaster, F. P. & Bemis, K. G. (1986) Hemodynamic and electrocardiographic effects of fluoxetine and its major metabolite, norfluoxetine, in anaesthetized dogs. Toxicology and Applied Pharmacology, 82, 70–79.Google Scholar
Suranyi-Cadotte, B. E., Dam, T. V. & Quirion, R. (1985) Antidepressant-anxiolytic interaction: decreased density of benzodiazepine receptors in rat brain following chronic administration of antidepressants. European Journal of Pharmacology, 106, 673–675.Google Scholar
Vetulani, J., Dingell, J. V. & Sulser, F. (1974) Effect of chronic treatment with desipramine (DMI) and iprindole (IP) on the norepinephrine (NE) sensitive adenylate cyclase system in slices of the rat limbic forebrain (LFS). The Pharmacologist, 16, 287.Google Scholar
Vetulani, J., Antkiewicz-Michaluk, L. & Rokosz-Pelc, A. (1984) Chronic administration of antidepressant drugs increases the density of cortical [3H] prazosin binding sites in the rat. Brain Research, 320, 360–362.Google Scholar
Wong, D. T. & Bymaster, F. P. (1976) The comparison of fluoxetine and nisoxetine with tricyclic antidepressants in blocking the neurotoxicity of p-chloroamphetamine and 6-hydroxydopamine in the rat brain. Research Communications in Chemical Pathology and Pharmacology, 15, 221–231.Google Scholar
Wong, D. T. & Bymaster, F. P. (1981) Subsensitivity of serotonin receptors after long-term treatment of rats with fluoxetine. Research Communications in Chemical Pathology and Pharmacology, 32, 41–51.Google ScholarPubMed
Wong, D. T. & Bymaster, F. P. (1984) Molecular pharmacology of fluoxetine, a new antidepressant. 14th CINP Congress Abstracts, 817, Collegium Internationale Neuro-Psychopharmacologicum.Google Scholar
Wong, D. T., Bymaster, F. P., Horng, J. S. & Molloy, B. B. (1975a) A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Journal of Pharmacology and Experimental Therapeutics, 193, 804–811.Google Scholar
Wong, D. T., Horng, J. S. & Bymaster, F. P. (1975b) dl-N-Methyl-3-(p-methoxyphenoxy)-3-phenylpropylamine hydrochloride. Lilly 94939, a potent inhibitor for uptake of norepinephrine into rat brain synaptosomes and heart. Life Sciences, 17, 755–760.Google Scholar
Wong, D. T., Threlkeld, P. G., Best, K. L. & Bymaster, F. P. (1982) A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain. Journal of Pharmacology and Experimental Therapeutics, 222, 61–65.Google Scholar
Wong, D. T., Bymaster, F. P., Reid, L. R. & Threlkeld, P. G. (1983) Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors. Biochemical Pharmacology, 32, 1287–1293.Google Scholar
Wong, D. T., Bymaster, F. P., Reid, L. R., Fuller, R. W. & Perry, K. W. (1985a) Inhibition of serotonin uptake by optical isomers of fluoxetine. Drug Development Research, 6, 397–403.Google Scholar
Wong, D. T., Reid, L. R., Bymaster, F. P. & Threlkeld, P. G. (1985b) Chronic effects of fluoxetine, a selective inhibitor of serotonin uptake, on neurotransmitter receptors. Journal of Neural Transmission, 64, 251–269.Google Scholar
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