Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT1A binding sites in 5-HT transporter knockout mice

The aim of the present study was to determine whether alterations in 5-hydr oxytryptamine (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 eval uated the dose-response and time course of 8-OH-DPAT-induced hypothermia an d 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 bloc ked by the 5-HT1A antagonist WAY-100635.8-OH-DPAT dose-dependently increase d 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 sig nificantly 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. [H-3]8-OH-DPAT- and [I-125]MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2 "-pyridinyl)-iodobenzamido]et hyl]piperazine]-binding sites in the hypothalamus and [I-125]MPPI-binding s ites 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 de sensitization of 5-HT1A receptor responses to 8-OH-DPAT, which may be a con sequence, at least in part, of the decrease in density of 5-HT1A receptors in the hypothalamus and dorsal raphe of 5-HTT-/- mice.