TY - JOUR T1 - Reduction of 5-Hydroxytryptamine (5-HT)<sub>1A</sub>-Mediated Temperature and Neuroendocrine Responses and 5-HT<sub>1A</sub> Binding Sites in 5-HT Transporter Knockout Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 999 LP - 1007 VL - 291 IS - 3 AU - Qian Li AU - Christine Wichems AU - Armin Heils AU - Louis D. Van de Kar AU - Klaus-Peter Lesch AU - Dennis L. Murphy Y1 - 1999/12/01 UR - http://jpet.aspetjournals.org/content/291/3/999.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -