Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors: Reductions in hypothalamic and midbrain Gi and Go proteins and in neuroendocrine responses to a 5-HT1A agonist

Q. Li, N. A. Muma, L. D. Van De Kar

Research output: Contribution to journalArticlepeer-review

Abstract

The time course of fluoxetine-induced desensitization of hypothalamic 5-hydroxytryptamine1A receptors was examined in rats. Daily injections of fluoxetine (10 mg/kg/day) for 0, 3, 7, 14 or 22 days gradually produced a shift to the right in the dose-response curve effects of 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) on plasma adrenal corticotropic hormone, corticosterone and oxytocin. A partial reduction was observed for the adrenal corticotropic hormone and oxytocin responses to 8-OH-DPAT (50 μg/kg s.c.) after 3 days, and a maximum reduction of all hormone responses was observed after 14 days of fluoxetine injections, when the adrenal corticotropic hormone and oxytocin responses to the 50-μg/kg dose of 8-OH-DPAT were virtually blocked. To begin to examine the mechanism of 5-hydroxytryptamine1A receptor desensitization, we determined levels of Gi and Go proteins in the hypothalamus, midbrain and frontal cortex by using immunoblots. The hypothalamic levels of Gi1 and Gi3 proteins were significantly reduced after 7 and 14 days of fluoxetine injections. The levels of Go and Gi2 proteins in the midbrain were significantly decreased after 3 days and remained reduced for the duration of fluoxetine injections. Fluoxetine did not reduce the concentrations of Gi and Go proteins in the frontal cortex at any time. The similarity in time course between fluoxetine-induced reductions in hormone responses to 8-OH-DPAT and the reduction in hypothalamic levels of Gi1 and Gi3 proteins suggests that a reduction in hypothalamic levels of Gi3 and/or Gi1 proteins plays a role in the gradual desensitization of 5-hydroxytryptamine1A receptors induced by fluoxetine.

Original languageEnglish (US)
Pages (from-to)1035-1042
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume279
Issue number2
StatePublished - Nov 1996
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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