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. 1993 Sep;110(1):355–359. doi: 10.1111/j.1476-5381.1993.tb13817.x

The effects of single and repeated anorectic doses of 5-hydroxytryptamine uptake inhibitors on indole levels in rat brain.

S Caccia 1, M Anelli 1, A M Codegoni 1, C Fracasso 1, S Garattini 1
PMCID: PMC2175989  PMID: 7693282

Abstract

1. The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5-hydroxytryptamine (5-HT) uptake inhibitors on the content of brain indoles were compared in rats in relation to the brain regional concentrations of unchanged drug and its known active metabolite. 2. Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 mumol kg-1), fluvoxamine (60 mumol kg-1), paroxetine (20 mumol kg-1) and sertraline (49 mumol kg-1) slightly reduced brain 5-hydroxyindoleacetic acid (5-HIAA), with regional differences, this being compatible with 5-HT uptake blockade. Only fluvoxamine and sertraline significantly enhanced the content of 5-HT in the cortex. 3. The regional sensitivity to the acute effect of a given drug was not related to any preferential drug distribution, as these compounds distributed almost uniformly in the brain areas considered (cortex, striatum and hippocampus). 4. Repeating the same doses twice daily, i.p. for 14 days, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertraline lowering both 5-HT and 5-HIAA in all the brain regions compared to pair-fed control animals, 1 h after the last dose. 5. One week later only fluoxetine-treated animals still had reduced brain 5-HT, this probably being related to the accumulation of its main metabolite norfluoxetine in rat brain after chronic dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Achilli G., Perego C., Ponzio F. Application of the dual-cell coulometric detector: a method for assaying monoamines and their metabolites. Anal Biochem. 1985 Jul;148(1):1–9. doi: 10.1016/0003-2697(85)90620-7. [DOI] [PubMed] [Google Scholar]
  2. Anelli M., Bizzi A., Caccia S., Codegoni A. M., Fracasso C., Garattini S. Anorectic activity of fluoxetine and norfluoxetine in mice, rats and guinea-pigs. J Pharm Pharmacol. 1992 Aug;44(8):696–698. doi: 10.1111/j.2042-7158.1992.tb05500.x. [DOI] [PubMed] [Google Scholar]
  3. Benfield P., Ward A. Fluvoxamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs. 1986 Oct;32(4):313–334. doi: 10.2165/00003495-198632040-00002. [DOI] [PubMed] [Google Scholar]
  4. Caccia S., Bizzi A., Coltro G., Fracasso C., Frittoli E., Mennini T., Garattini S. Anorectic activity of fluoxetine and norfluoxetine in rats: relationship between brain concentrations and in-vitro potencies on monoaminergic mechanisms. J Pharm Pharmacol. 1992 Mar;44(3):250–254. doi: 10.1111/j.2042-7158.1992.tb03592.x. [DOI] [PubMed] [Google Scholar]
  5. Caccia S., Cappi M., Fracasso C., Garattini S. Influence of dose and route of administration on the kinetics of fluoxetine and its metabolite norfluoxetine in the rat. Psychopharmacology (Berl) 1990;100(4):509–514. doi: 10.1007/BF02244004. [DOI] [PubMed] [Google Scholar]
  6. Caccia S., Fracasso C., Garattini S., Guiso G., Sarati S. Effects of short- and long-term administration of fluoxetine on the monoamine content of rat brain. Neuropharmacology. 1992 Apr;31(4):343–347. doi: 10.1016/0028-3908(92)90066-x. [DOI] [PubMed] [Google Scholar]
  7. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  8. Dechant K. L., Clissold S. P. Paroxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness. Drugs. 1991 Feb;41(2):225–253. doi: 10.2165/00003495-199141020-00007. [DOI] [PubMed] [Google Scholar]
  9. Ferguson J. M., Feighner J. P. Fluoxetine-induced weight loss in overweight non-depressed humans. Int J Obes. 1987;11 (Suppl 3):163–170. [PubMed] [Google Scholar]
  10. Foglia J. P., Birder L. A., Perel J. M. Determination of fluvoxamine in human plasma by high-performance liquid chromatography with ultraviolet detection. J Chromatogr. 1989 Oct 27;495:295–302. doi: 10.1016/s0378-4347(00)82635-3. [DOI] [PubMed] [Google Scholar]
  11. Gobbi M., Frittoli E., Mennini T., Garattini S. Releasing activities of d-fenfluramine and fluoxetine on rat hippocampal synaptosomes preloaded with [3H]serotonin. Naunyn Schmiedebergs Arch Pharmacol. 1992 Jan;345(1):1–6. doi: 10.1007/BF00175461. [DOI] [PubMed] [Google Scholar]
  12. Johnson A. M. An overview of the animal pharmacology of paroxetine. Acta Psychiatr Scand Suppl. 1989;350:14–20. doi: 10.1111/j.1600-0447.1989.tb07161.x. [DOI] [PubMed] [Google Scholar]
  13. Koe B. K., Weissman A., Welch W. M., Browne R. G. Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin. J Pharmacol Exp Ther. 1983 Sep;226(3):686–700. [PubMed] [Google Scholar]
  14. Leonard B. E. Pharmacological effects of serotonin reuptake inhibitors. J Clin Psychiatry. 1988 Aug;49 (Suppl):12–17. [PubMed] [Google Scholar]
  15. Murdoch D., McTavish D. Sertraline. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive-compulsive disorder. Drugs. 1992 Oct;44(4):604–624. doi: 10.2165/00003495-199244040-00007. [DOI] [PubMed] [Google Scholar]
  16. Nathan C., Rolland Y. Pharmacological treatments that affect CNS activity: serotonin. Ann N Y Acad Sci. 1987;499:277–296. doi: 10.1111/j.1749-6632.1987.tb36219.x. [DOI] [PubMed] [Google Scholar]
  17. Ross S. B., Hall H., Renyi A. L., Westerlund D. Effects of zimelidine on serotoninergic and noradrenergic neurons after repeated administration in the rat. Psychopharmacology (Berl) 1981;72(3):219–225. doi: 10.1007/BF00431820. [DOI] [PubMed] [Google Scholar]
  18. Sarkissian C. F., Wurtman R. J., Morse A. N., Gleason R. Effects of fluoxetine or D-fenfluramine on serotonin release from, and levels in, rat frontal cortex. Brain Res. 1990 Oct 8;529(1-2):294–301. doi: 10.1016/0006-8993(90)90840-8. [DOI] [PubMed] [Google Scholar]
  19. Schmidt M. J., Fuller R. W., Wong D. T. Fluoxetine, a highly selective serotonin reuptake inhibitor: a review of preclinical studies. Br J Psychiatry Suppl. 1988 Sep;(3):40–46. [PubMed] [Google Scholar]
  20. Simpson R. J., Lawton D. J., Watt M. H., Tiplady B. Effect of zimelidine, a new antidepressant, on appetite and body weight. Br J Clin Pharmacol. 1981 Jan;11(1):96–98. doi: 10.1111/j.1365-2125.1981.tb01112.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Smedegaard J., Christiansen P., Skrumsager B. "Treatment of obesity by femoxetine a selective 5 HT reuptake inhibitor'. Int J Obes. 1981;5(4):377–378. [PubMed] [Google Scholar]
  22. Tremaine L. M., Welch W. M., Ronfeld R. A. Metabolism and disposition of the 5-hydroxytryptamine uptake blocker sertraline in the rat and dog. Drug Metab Dispos. 1989 Sep-Oct;17(5):542–550. [PubMed] [Google Scholar]
  23. Wong D. T., Fuller R. W. Serotonergic mechanisms in feeding. Int J Obes. 1987;11 (Suppl 3):125–133. [PubMed] [Google Scholar]

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