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 μg/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 Gzproteins were unaltered, indicating that reductions in Gzand 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.
Footnotes
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Send reprint requests to: Louis D. Van de Kar, Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Avenue, Maywood IL 60153.
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1 Supported in part by United States Public Health Service Grant NS34153 (LDVdK). A portion of this research was previously presented at the Society for Neuroscience 27th Annual Meeting (1997; 385.4).
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine (serotonin)
- 8-OH-DPAT
- 8-hydroxy-2-(dipropylamino)tetralin
- ACTH
- adrenocorticotropic hormone
- ANOVA
- analysis of variance
- DOI
- (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl
- integrated optical density
- IOD
- SDS
- sodium dodecyl sulfate
- SSRI
- selective serotonin reuptake inhibitor
- Received March 19, 1998.
- Accepted July 28, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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