Enhanced responsivity of 5-HT(2A) receptors at warm ambient temperatures is responsible for the augmentation of the 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia.

Warm ambient temperature facilitates hyperthermia and other neurotoxic responses elicited by psychogenic drugs such as MDMA and methamphetamine. However, little is known about the neural mechanism underlying such effects. In the present study, we tested the hypothesis that a warm ambient temperature may enhance the responsivity of 5-HT(2A) receptors in the central nervous system and thereafter cause an augmented response to 5-HT(₂A) receptor agonists. This hypothesis was tested by measuring changes in body-core temperature in response to the 5-HT(2A) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) administered at four different ambient temperature levels: 12 °C (cold), 22 °C (standard), 27 °C (thermoneutral zone) and 32 °C (warm). It was found that DOI only evoked a small increase in body-core temperature at the standard (22 °C) or thermoneutral ambient temperature (27 °C). In contrast, there was a large increase in body-core temperature when the experiments were conducted at the warmer ambient temperature (32 °C). Interestingly, the effect of DOI at the cold ambient temperature of 12 °C was significantly reduced. Moreover, the ambient temperature-dependent response to DOI was completely blocked by pretreatment with the 5-HT(₂A) receptor antagonist ketanserin. Taken together, these findings support the hypothesis that 5-HT(₂A) receptors may be responsible for some neurotoxic effects of psychogenic drugs in the central nervous system, the activity of which is functionally inhibited at cold but enhanced at warm ambient temperature in contrast to that at standard experimental conditions.