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Research ArticleNEUROPHARMACOLOGY

Coadministration of 5-Hydroxytryptamine1AAntagonist WAY-100635 Prevents Fluoxetine-Induced Desensitization of Postsynaptic 5-Hydroxytryptamine1A Receptors in Hypothalamus

Florence Serres, Nancy A. Muma, Daní K. Raap, Francisca Garcia, George Battaglia and Louis D. Van de Kar
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 296-301;
Florence Serres
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Nancy A. Muma
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Daní K. Raap
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Francisca Garcia
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George Battaglia
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Louis D. Van de Kar
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Abstract

Treatment with selective serotonin reuptake inhibitors induces a desensitization of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)1A receptors in humans and rats. This study investigated whether fluoxetine-induced desensitization is due to overactivation of postsynaptic 5-HT1A receptors; whether blockade of somatodendritic 5-HT1A autoreceptors accelerates this desensitization; and whether desensitization is associated with a reduction of Gz proteins, which couple to 5-HT1A receptors. WAY-100635 was tested at low doses (0.03–0.3 mg/kg), which antagonize somatodendritic 5-HT1Aautoreceptors in the raphe nuclei, and at a higher dose (1 mg/kg), which completely blocks postsynaptic 5-HT1A receptors. Plasma levels of oxytocin and adrenal corticotrophic hormone (corticotropin) were measured as peripheral indicators of hypothalamic 5-HT1A receptor function. Daily injections of fluoxetine (10 mg/kg/day i.p.) for 2 days did not desensitize 5-HT1Areceptors but three daily injections of fluoxetine produced a partial desensitization of the hormone responses to (±)-8-hydroxy-2-dipropylaminoetetralin (50 μg/kg s.c.). WAY-100635 (0.03–0.3 mg/kg) did not accelerate or potentiate the fluoxetine-induced desensitization of 5-HT1A receptors. However, WAY-100635 at a dose that completely blocks postsynaptic 5-HT1A receptors (1.0 mg/kg) completely prevented the fluoxetine-induced desensitization of 5-HT1A receptors. These data demonstrate that at least 3 days of fluoxetine exposure is required to produce a homologous desensitization of hypothalamic 5-HT1A receptors. Although previous studies indicate that injections of fluoxetine for 14 days produce a reduction of Gz protein levels in the hypothalamus, the levels of Gz proteins were not affected by either fluoxetine or WAY-100635. Alternative mechanisms mediating the initial stages of 5-HT1A receptor desensitization could involve post-translational modifications in the 5-HT1Areceptor-Gz protein-signaling cascade.

Footnotes

  • Send reprint requests to: Louis D. Van de Kar, Ph.D., Department of Pharmacology, Loyola University of Chicago, School of Medicine, 2160 South First Ave., Maywood, IL 60153. E-mail:lvandek{at}luc.edu

  • ↵1 This study was supported in part by U.S. Public Health Service Grants NS34153 (to L.D.V.D.K.) and NS38509 (to N.A.M.), National Alliance for Research on Schizophrenia and Depression (to D.K.R.), and the Loyola University Neuroscience and Aging Institute postdoctoral program (to F.S.).

  • ↵2 Current address: Lilly Research Centre, Erl Wood Manor, Sunninghill Rd., Windlesham Surrey GU20 6PH, UK.

  • ↵3 Current address: Department of Psychology, University of Alaska Fairbanks, Fairbanks, AK 99775.

  • Abbreviations:
    5-HT
    5-hydroxytryptamine
    SSRI
    selective serotonin reuptake inhibitor
    ACTH
    adrenal corticotrophic hormone (corticotropin)
    WAY-100635
    N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride
    8-OH-DPAT
    (±)-8-hydroxy-2-dipropylaminoetetralin
    IOD
    integrated optical density
    • Received December 20, 1999.
    • Accepted March 10, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleNEUROPHARMACOLOGY

Coadministration of 5-Hydroxytryptamine1AAntagonist WAY-100635 Prevents Fluoxetine-Induced Desensitization of Postsynaptic 5-Hydroxytryptamine1A Receptors in Hypothalamus

Florence Serres, Nancy A. Muma, Daní K. Raap, Francisca Garcia, George Battaglia and Louis D. Van de Kar
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 296-301;

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Research ArticleNEUROPHARMACOLOGY

Coadministration of 5-Hydroxytryptamine1AAntagonist WAY-100635 Prevents Fluoxetine-Induced Desensitization of Postsynaptic 5-Hydroxytryptamine1A Receptors in Hypothalamus

Florence Serres, Nancy A. Muma, Daní K. Raap, Francisca Garcia, George Battaglia and Louis D. Van de Kar
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 296-301;
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