TY - JOUR
T1 - Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors
T2 - Reductions in hypothalamic and midbrain Gi and Go proteins and in neuroendocrine responses to a 5-HT1A agonist
AU - Li, Q.
AU - Muma, N. A.
AU - Van De Kar, L. D.
N1 - Copyright:
Copyright 2004 Elsevier Science B.V., Amsterdam. All rights reserved.
PY - 1996/11
Y1 - 1996/11
N2 - 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.
AB - 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.
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M3 - Article
C2 - 8930214
AN - SCOPUS:0030433045
SN - 0022-3565
VL - 279
SP - 1035
EP - 1042
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -