Abstract
In the present study, we examined denervation-induced changes in the sensitivity of hypothalamic postsynaptic serotonin1A(5-HT1A) receptor function with respect to changes in the dose-dependent elevation in plasma hormones [adrenocorticotropic hormone (ACTH), corticosterone, prolactin, oxytocin, prolactin, renin and vasopressin] by the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT). Rats received intracerebroventricular (i.c.v.) injections of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or vehicle (0.1% ascorbate in saline) 3 weeks before challenge with increasing doses of 8-OH-DPAT (0, 10, 50 or 200 μg/kg s.c.). The effectiveness of 5,7-DHT-induced destruction of serotonergic neurons was confirmed by a 93% reduction in [3H]paroxetine-labeled 5-HT uptake sites in the hypothalamus. No changes in basal levels of ACTH, corticosterone, oxytocin, prolactin, renin and vasopressin were observed in rats that received i.c.v. 5,7-DHT injections. The dose-response curves for 8-OH-DPAT-induced elevations of plasma corticosterone and prolactin levels were shifted to the left in rats treated with 5,7-DHT, whereas no significant difference in the ACTH dose-response curve was observed between rats treated with vehicle and rats treated with 5,7-DHT. In contrast, the maximal oxytocin response to 8-OH-DPAT was attenuated in rats treated with 5,7-DHT. A 5,7-DHT-induced decline in the synthesis of oxytocin could explain this phenomenon. Although 8-OH-DPAT did not increase plasma levels of renin or vasopressin in rats treated with vehicle, 8-OH-DPAT produced an elevation (75%) in plasma renin concentration but not in vasopressin levels in rats that received i.c.v. injections of 5,7-DHT. No change was observed in [3H]8-OH-DPAT labeled 5-HT1A receptors in the hypothalamus. In summary, denervation of hypothalamic serotonergic nerve terminals produces supersensitivity of some neuroendocrine responses to 8-OH-DPAT independent of changes in the density of hypothalamic 5-HT1A receptors.
Footnotes
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Send reprint requests to: Louis D. Van de Kar, Ph.D., Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Avenue, Maywood IL 60153. E-mail:lvandek{at}luc.edu
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↵1 This work was supported in part by United States Public Health Service Grants MH45812, NS34153 (L.D.V. de K.) and DA07741 (G.B.).
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↵2 Present address: NIMH, 9000 Rockville Pike, Bethesda, MD 20892-1264.
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↵3 Present address: Northwestern University Institute for Neuroscience, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, IL 60611.
- Abbreviations:
- ACTH
- adrenocorticotropic hormone
- ANOVA
- analysis of variance
- 5-HT
- 5-hydroxytryptamine (serotonin)
- CRH
- corticotropin-releasing hormone
- PVN
- paraventricular nucleus
- 8-OH-DPAT
- 8-hydroxy-2-(dipropylamino)tetralin
- Received November 10, 1997.
- Accepted March 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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