Hedlund Peter B, Kelly Lisa, Mazur Curt, Lovenberg Timothy, Sutcliffe J Gregor, Bonaventure Pascal
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Eur J Pharmacol. 2004 Mar 8;487(1-3):125-32. doi: 10.1016/j.ejphar.2004.01.031.
Studies using selective drugs and knockout mice have demonstrated that the 5-HT(7) receptor plays an instrumental role in serotonin-induced hypothermia. There is also evidence supporting an involvement of the 5-HT(1A) receptor, although mainly from studies using 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT(1A/7) receptor agonist. Here we studied the effects of 8-OH-DPAT and selective antagonists for the 5-HT(1A) and 5-HT(7) receptors on body temperature in rats, wild-type (5-HT(7)(+/+)) mice and knockout (5-HT(7)(-/-)) mice. At lower doses (0.3-0.6 mg/kg, i.p.), 8-OH-DPAT decreased body temperature in 5-HT(7)(+/+) mice but not in 5-HT(7)(-/-) mice. At a higher dose (1 mg/kg, i.p.) 8-OH-DPAT induced hypothermia in both 5-HT(7)(-/-) and 5-HT(7)(+/+) mice. The 5-HT(1A) receptor antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide (WAY-100135) (10 mg/kg, i.p.) inhibited the effect of 8-OH-DPAT at all doses in rats and mice. In 5-HT(7)(+/+) mice the selective 5-HT(7) receptor antagonist (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) (10 mg/kg, i.p.) fully inhibited the hypothermia induced by 0.3 mg/kg 8-OH-DPAT, but not that of higher doses. In rats, SB-269970 caused a 60% inhibition of the hypothermia induced by 0.3 mg/kg 8-OH-DPAT. Thus, both 5-HT(7) and 5-HT(1A) receptors are involved in a complex manner in thermoregulation, with the 5-HT(7) receptor being more important at lower, possibly more physiological, concentrations.
使用选择性药物和基因敲除小鼠的研究表明，5-羟色胺（7）受体在血清素诱导的体温过低中起重要作用。也有证据支持5-羟色胺（1A）受体参与其中，尽管主要来自使用8-羟基-2（二正丙基氨基）四氢萘（8-OH-DPAT）的研究，8-OH-DPAT是一种5-羟色胺（1A/7）受体激动剂。在此，我们研究了8-OH-DPAT以及5-羟色胺（1A）和5-羟色胺（7）受体的选择性拮抗剂对大鼠、野生型（5-羟色胺（7）（+/+））小鼠和基因敲除（5-羟色胺（7）（-/-））小鼠体温的影响。较低剂量（0.3-0.6毫克/千克，腹腔注射）时，8-OH-DPAT可降低5-羟色胺（7）（+/+）小鼠的体温，但对5-羟色胺（7）（-/-）小鼠无效。较高剂量（1毫克/千克，腹腔注射）时，8-OH-DPAT可使5-羟色胺（7）（-/-）和5-羟色胺（7）（+/+）小鼠均出现体温过低。5-羟色胺（1A）受体拮抗剂（S）-N-叔丁基-3-（4-（2-甲氧基苯基）哌嗪-1-基）-2-苯基丙酰胺（WAY-100135）（10毫克/千克，腹腔注射）在所有剂量下均能抑制大鼠和小鼠体内8-OH-DPAT的作用。在5-羟色胺（7）（+/+）小鼠中，选择性5-羟色胺（7）受体拮抗剂（R）-3-（2-（2-（4-甲基哌啶-1-基）-乙基）吡咯烷-1-磺酰基）苯酚（SB-269970）（10毫克/千克，腹腔注射）可完全抑制0.3毫克/千克8-OH-DPAT诱导的体温过低，但对更高剂量则无效。在大鼠中，SB-269970可使0.3毫克/千克8-OH-DPAT诱导的体温过低受到60%的抑制。因此，5-羟色胺（7）和5-羟色胺（1A）受体以复杂的方式参与体温调节，在较低的、可能更接近生理水平的浓度下，5-羟色胺（7）受体更为重要。
