Abstract
The aim of the present study was to determine whether alterations in 5-hydroxytryptamine (5-HT)1A receptors would be found in knockout mice lacking the serotonin transporter (5-HTT). Hypothermic and neuroendocrine responses to the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) were used to examine the function of 5-HT1A receptors. Initial studies evaluated the dose-response and time course of 8-OH-DPAT-induced hypothermia and hormone secretion in normal CD-1 mice (the background strain of the 5-HTT knockout mice). 8-OH-DPAT dose-dependently produced hypothermic responses that peaked at 20 min postinjection. 8-OH-DPAT-induced hypothermia was blocked by the 5-HT1A antagonist WAY-100635. 8-OH-DPAT dose-dependently increased the concentrations of plasma oxytocin, corticotropin, and corticosterone. In the 5-HTT knockout (−/−) mice, the hypothermic response to 8-OH-DPAT (0.1 mg/kg s.c.) was completely abolished. Furthermore, 5-HTT−/− mice had significantly attenuated plasma oxytocin and corticosterone responses to 8-OH-DPAT. No significant changes in the hypothermic or hormonal responses to 8-OH-DPAT were observed in heterozygous (5-HTT+/−) mice. [3H]8-OH-DPAT- and [125I]MPPI [4-(2′-methoxyphenyl)-1-[2′-[N-(2"-pyridinyl)-iodobenzamido]ethyl]piperazine]-binding sites in the hypothalamus and [125I]MPPI-binding sites in the dorsal raphe were significantly decreased in 5-HTT−/− mice. The results indicate that lack of the 5-HTT is associated with a functional desensitization of 5-HT1A receptor responses to 8-OH-DPAT, which may be a consequence, at least in part, of the decrease in density of 5-HT1A receptors in the hypothalamus and dorsal raphe of 5-HTT−/− mice.
Footnotes
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Send reprint requests to: Qian Li, Ph.D., Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health Clinical Center, Room 3D41, 10 Center Dr., MSC-1264, Bethesda, MD 20892-1264. E-mail:qianli{at}codon.nih.gov
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↵1 K.-P.L. is supported by the Hermann and Lilly Schilling Foundation.
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine (serotonin)
- 5-HTT
- 5-hydroxytryptamine transporter
- 8-OH-DPAT
- 8-hydroxy-2-(di-n-propylamino)tetraline
- MPPI
- 4-(2′-methoxyphenyl)-1-[2′-[N-(2"-pyridinyl)-iodobenzamido]ethyl]piperazine
- WAY-100635
- (N-[2-(4(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridyl)cyclohexanecarboxamide
- ACTH
- corticotropin
- SRI
- serotonin reuptake inhibitor
- Received March 26, 1999.
- Accepted August 7, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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