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Objective: Thermoregulation is a vital function in both humans and animals with the serotonin (5-HT) system, in particular the 5-HT1A receptor, playing a major role. Activating 5-HT1A receptors by the 5 HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) leads to reduced body temperature. While there is consensus that hypothermia is induced by the stimulation of postsynaptic 5-HT1A receptors in rats and humans, the regulatory mechanisms in mice are less clear. In our group, within phenotyping a transgenic mouse line permanently overexpressing the 5-HT1A receptor in serotonergic projection areas, Bert et al. (2008, PMID: 18396339) revealed exaggerated 8-OH-DPAT-provoked hypothermic response. Thus, the objective of the present study was to substantiate the contribution of postsynaptic 5-HT1A receptors to thermoregulation, more precisely to the hypothermic effect of 8-OH-DPAT, in mice.
Methods: We used radio telemetry technique to monitor the basal body temperature and the hypothermic effect of different doses of 8-OH-DPAT (0.1 mg/kg – 4 mg/kg i. p.) in male transgenic mice in comparison to NMRI wild-type males. Additionally, we investigated whether reduction of serotonergic activity by pretreatment with the 5 HT synthesis inhibitor parachlorophenylalanine (PCPA; 100 mg/kg, i. p. on four consecutive days) would alter the effects of 8-OH-DPAT on body temperature in transgenic mice postsynaptically overexpressing the 5 HT1A receptor.
Results: 5-HT1A overexpressing mice revealed lower levels of basal body temperature than wild types (transgenic mice: 36.0 °C; NMRI wild-type mice: 37.4 °C). In both genotypes, systemic administration of 8-OH-DPAT dose-dependently decreased body temperature, being significantly more pronounced in mutant mice (-2.8 °C compared to -1.5 °C in NMRI wild types). Dose response curves of 8-OH-DPAT revealed an ED50 = 0.4 mg/kg in transgenic and an ED50 = 0.57 mg/kg in NMRI wild-type mice. PCPA pretreatment did not alter the hypothermic response to 8-OH-DPAT in mice.
Conclusions: The dose-response curves indicate a higher potency of 8-OH-DPAT in transgenic mice. The exaggerated hypothermic response to 8-OH-DPAT in mutant mice implies that postsynaptic 5 HT1A receptors could be involved in thermoregulatory function in mice. This assumption is further confirmed by the fact that 8-OH-DPAT-evoked thermal responses were not influenced by pretreatment with PCPA, most notably in transgenic mice overexpressing 5-HT1A receptors postsynaptically.