Stress-induced hyperthermia and basal body temperature are mediated by different 5-HT1A receptor populations: A study in SERT knockout rats

Disturbances in the serotonergic system are implicated in many central nervous system disorders. The serotonin transporter (SERT) regulates the serotonin homeostasis in the synapse. We recently developed a rat which lacks the serotonin transporter (SERT−/−). It is likely that adaptive changes take place at the level of pre- and postsynaptic 5-HT receptors. Because autonomic responses are often used to measure 5-HT1A receptor function, we analysed these responses by examining the effects of a 5-HT1A receptor agonist and antagonist under in vivo conditions in the SERT−/− rat. Moreover, we studied the effect of a mild stressor on the body temperature (stress-induced hyperthermia) because of the known involvement of 5-HT1A receptors in this phenomenon. Results show that core body temperature did not differ between genotypes under basal, non-stressed conditions. Compared to SERT+/+ rats, stress-induced hyperthermia was reduced in SERT−/− rats. The 5-HT1A receptor agonist [R(+)-N-(2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4-benzodioxin-5-yl)-1-piperazininyl]ethyl)-4-fluorobenzoamide HCl (flesinoxan) reduced stress-induced hyperthermia in both genotypes. The flesinoxan-induced hypothermia in SERT+/+ rats was blocked by the 5-HT1A receptor antagonist [N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexane carboxamide 3HCl (WAY100635). Moreover, WAY100635-induced hyperthermia in SERT−/−, but not in SERT+/+ rats. In SERT−/− rats, WAY100635 completely blocked the flesinoxan-induced reduction of stress-induced hyperthermia. Interestingly, flesinoxan-induced hypothermia was absent in SERT−/− rats. It is concluded that the SERT knockout rat reveals that 5-HT1A receptors modulating stress-induced hyperthermia belong to a population of receptors that differs from that involved in hypothermia.