Tags

Type your tag names separated by a space and hit enter

Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 prevents fluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A) receptors in hypothalamus.
J Pharmacol Exp Ther. 2000 Jul; 294(1):296-301.JP

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-HT(1A) receptors; whether blockade of somatodendritic 5-HT(1A) autoreceptors accelerates this desensitization; and whether desensitization is associated with a reduction of Gz proteins, which couple to 5-HT(1A) receptors. WAY-100635 was tested at low doses (0.03-0.3 mg/kg), which antagonize somatodendritic 5-HT(1A) autoreceptors in the raphe nuclei, and at a higher dose (1 mg/kg), which completely blocks postsynaptic 5-HT(1A) receptors. Plasma levels of oxytocin and adrenal corticotrophic hormone (corticotropin) were measured as peripheral indicators of hypothalamic 5-HT(1A) receptor function. Daily injections of fluoxetine (10 mg/kg/day i.p.) for 2 days did not desensitize 5-HT(1A) receptors but three daily injections of fluoxetine produced a partial desensitization of the hormone responses to (+/-)-8-hydroxy-2-dipropylaminoetetralin (50 microg/kg s.c.). WAY-100635 (0.03-0.3 mg/kg) did not accelerate or potentiate the fluoxetine-induced desensitization of 5-HT(1A) receptors. However, WAY-100635 at a dose that completely blocks postsynaptic 5-HT(1A) receptors (1.0 mg/kg) completely prevented the fluoxetine-induced desensitization of 5-HT(1A) receptors. These data demonstrate that at least 3 days of fluoxetine exposure is required to produce a homologous desensitization of hypothalamic 5-HT(1A) 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-HT(1A) receptor desensitization could involve post-translational modifications in the 5-HT(1A) receptor-Gz protein-signaling cascade.

Authors+Show Affiliations

Loyola University of Chicago, Stritch School of Medicine, Department of Pharmacology, Maywood, Illinois 60153, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10871325

Citation

Serres, F, et al. "Coadministration of 5-hydroxytryptamine(1A) Antagonist WAY-100635 Prevents Fluoxetine-induced Desensitization of Postsynaptic 5-hydroxytryptamine(1A) Receptors in Hypothalamus." The Journal of Pharmacology and Experimental Therapeutics, vol. 294, no. 1, 2000, pp. 296-301.
Serres F, Muma NA, Raap DK, et al. Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 prevents fluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A) receptors in hypothalamus. J Pharmacol Exp Ther. 2000;294(1):296-301.
Serres, F., Muma, N. A., Raap, D. K., Garcia, F., Battaglia, G., & Van de Kar, L. D. (2000). Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 prevents fluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A) receptors in hypothalamus. The Journal of Pharmacology and Experimental Therapeutics, 294(1), 296-301.
Serres F, et al. Coadministration of 5-hydroxytryptamine(1A) Antagonist WAY-100635 Prevents Fluoxetine-induced Desensitization of Postsynaptic 5-hydroxytryptamine(1A) Receptors in Hypothalamus. J Pharmacol Exp Ther. 2000;294(1):296-301. PubMed PMID: 10871325.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 prevents fluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A) receptors in hypothalamus. AU - Serres,F, AU - Muma,N A, AU - Raap,D K, AU - Garcia,F, AU - Battaglia,G, AU - Van de Kar,L D, PY - 2000/6/28/pubmed PY - 2000/8/1/medline PY - 2000/6/28/entrez SP - 296 EP - 301 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 294 IS - 1 N2 - 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-HT(1A) receptors; whether blockade of somatodendritic 5-HT(1A) autoreceptors accelerates this desensitization; and whether desensitization is associated with a reduction of Gz proteins, which couple to 5-HT(1A) receptors. WAY-100635 was tested at low doses (0.03-0.3 mg/kg), which antagonize somatodendritic 5-HT(1A) autoreceptors in the raphe nuclei, and at a higher dose (1 mg/kg), which completely blocks postsynaptic 5-HT(1A) receptors. Plasma levels of oxytocin and adrenal corticotrophic hormone (corticotropin) were measured as peripheral indicators of hypothalamic 5-HT(1A) receptor function. Daily injections of fluoxetine (10 mg/kg/day i.p.) for 2 days did not desensitize 5-HT(1A) receptors but three daily injections of fluoxetine produced a partial desensitization of the hormone responses to (+/-)-8-hydroxy-2-dipropylaminoetetralin (50 microg/kg s.c.). WAY-100635 (0.03-0.3 mg/kg) did not accelerate or potentiate the fluoxetine-induced desensitization of 5-HT(1A) receptors. However, WAY-100635 at a dose that completely blocks postsynaptic 5-HT(1A) receptors (1.0 mg/kg) completely prevented the fluoxetine-induced desensitization of 5-HT(1A) receptors. These data demonstrate that at least 3 days of fluoxetine exposure is required to produce a homologous desensitization of hypothalamic 5-HT(1A) 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-HT(1A) receptor desensitization could involve post-translational modifications in the 5-HT(1A) receptor-Gz protein-signaling cascade. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/10871325/Coadministration_of_5_hydroxytryptamine_1A__antagonist_WAY_100635_prevents_fluoxetine_induced_desensitization_of_postsynaptic_5_hydroxytryptamine_1A__receptors_in_hypothalamus_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10871325 DB - PRIME DP - Unbound Medicine ER -