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Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins.
J Pharmacol Exp Ther 1999; 288(1):98-106JP

Abstract

The present studies examined the dose-response relationship of fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptors, as measured from the reduced neuroendocrine responses to a 5-HT1A agonist. Because hypothalamic Gz proteins mediate the ACTH and oxytocin responses to 5-HT1A receptor activation, we also determined the effect of fluoxetine on the levels of Gz proteins in the hypothalamus. Rats were injected daily for 14 days with saline or with fluoxetine doses of 0.3, 1, 3, 5, 7. 5, or 10 mg/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, ACTH, and corticosterone responses to the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 50 micrograms/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine responses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maximally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic levels of Gz protein were reduced by both the 7.5 and 10 mg/kg/day doses of fluoxetine, whereas Gi1 protein levels were reduced only after the highest dose (10 mg/kg/day) of fluoxetine. Gi2, Gi3, and Go levels were not reduced by any fluoxetine dose. Cytosolic levels of Gi1 and Gz proteins were unaltered, indicating that reductions in Gz and Gi1 proteins are not caused by a redistribution of the proteins from the membrane into the cytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptor systems is dose-dependent and may be caused in part by reductions in the hypothalamic levels of Gz proteins.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

9862759

Citation

Raap, D K., et al. "Daily Injections of Fluoxetine Induce Dose-dependent Desensitization of Hypothalamic 5-HT1A Receptors: Reductions in Neuroendocrine Responses to 8-OH-DPAT and in Levels of Gz and Gi Proteins." The Journal of Pharmacology and Experimental Therapeutics, vol. 288, no. 1, 1999, pp. 98-106.
Raap DK, Evans S, Garcia F, et al. Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins. J Pharmacol Exp Ther. 1999;288(1):98-106.
Raap, D. K., Evans, S., Garcia, F., Li, Q., Muma, N. A., Wolf, W. A., ... Van De Kar, L. D. (1999). Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins. The Journal of Pharmacology and Experimental Therapeutics, 288(1), pp. 98-106.
Raap DK, et al. Daily Injections of Fluoxetine Induce Dose-dependent Desensitization of Hypothalamic 5-HT1A Receptors: Reductions in Neuroendocrine Responses to 8-OH-DPAT and in Levels of Gz and Gi Proteins. J Pharmacol Exp Ther. 1999;288(1):98-106. PubMed PMID: 9862759.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins. AU - Raap,D K, AU - Evans,S, AU - Garcia,F, AU - Li,Q, AU - Muma,N A, AU - Wolf,W A, AU - Battaglia,G, AU - Van De Kar,L D, PY - 1998/12/23/pubmed PY - 1998/12/23/medline PY - 1998/12/23/entrez SP - 98 EP - 106 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 288 IS - 1 N2 - The present studies examined the dose-response relationship of fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptors, as measured from the reduced neuroendocrine responses to a 5-HT1A agonist. Because hypothalamic Gz proteins mediate the ACTH and oxytocin responses to 5-HT1A receptor activation, we also determined the effect of fluoxetine on the levels of Gz proteins in the hypothalamus. Rats were injected daily for 14 days with saline or with fluoxetine doses of 0.3, 1, 3, 5, 7. 5, or 10 mg/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, ACTH, and corticosterone responses to the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 50 micrograms/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine responses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maximally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic levels of Gz protein were reduced by both the 7.5 and 10 mg/kg/day doses of fluoxetine, whereas Gi1 protein levels were reduced only after the highest dose (10 mg/kg/day) of fluoxetine. Gi2, Gi3, and Go levels were not reduced by any fluoxetine dose. Cytosolic levels of Gi1 and Gz proteins were unaltered, indicating that reductions in Gz and Gi1 proteins are not caused by a redistribution of the proteins from the membrane into the cytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptor systems is dose-dependent and may be caused in part by reductions in the hypothalamic levels of Gz proteins. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9862759/Daily_injections_of_fluoxetine_induce_dose_dependent_desensitization_of_hypothalamic_5_HT1A_receptors:_reductions_in_neuroendocrine_responses_to_8_OH_DPAT_and_in_levels_of_Gz_and_Gi_proteins_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9862759 DB - PRIME DP - Unbound Medicine ER -