We assess the effects of
ipsapirone (a
5-HT1A receptor agonist),
ketanserin (a
5-HT2A receptor antagonist), (-)-
pindolol (a
5-HT1A receptor antagonist), and DOI (a
5-HT2A receptor agonist) on
heatstroke in a rat model. Animals, under
urethane anesthesia, were exposed to high ambient temperature of 42 degrees C until mean arterial pressure and local cerebral blood flow in the striatum began to decrease, which was arbitrarily defined as the onset of
heatstroke. Normothermic controls were exposed to room temperature of 24 degrees C. In rats treated with
normal saline immediately before the initiation of heat stress, the values for survival time were found to be 21 to 25 min. Systemic administration of
ipsapirone (10 mg/kg) or
ketanserin (2 mg/kg) immediately before the initiation of heat stress significantly increased the survival time to new values of 92 to 104 min. Combined treatment with
ipsapirone and
ketanserin had additive effects (survival time of 156-194 min). In contrast, systemic administration of (-)-
pindolol (2 mg/kg) or DOI (2 mg/kg) significantly decreased the survival time to new values of 2 to 3 min. In vehicle-treated
heatstroke rats, the values for core temperature, intracranial pressure, and the extracellular levels of cellular
ischemia (e.g.,
glutamate and
lactate/
pyruvate ratio) or damage (e.g.,
glycerol) markers and neuronal damage scores in striatum were significantly higher than those of normothermic controls. On the other hand, the values for mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and brain partial pressure of O2 were significantly lower than those of normothermic controls. The
heatstroke-
induced hyperthermia, arterial
hypotension, intracranial hypertension, cerebral hypoperfusion and
hypoxia, and increased levels of cellular
ischemia and damage markers in striatum were all significantly attenuated by prior administration of
ipsapirone or
ketanserin. The present results strongly suggest that previous activation of 5-HT1A receptors or antagonism of 5-HT2A receptors protects against
heatstroke by reducing circulatory
shock and
cerebral ischemia, whereas prior antagonism of 5-HT1A receptors or activation of 5-HT2A receptors exacerbates
heatstroke.