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Abstract:  Previous studies have demonstrated that serotonin (5-HT) syndromes, particularly for the malignant cases, can be alleviated by ice water mists, cooling blankets and many other external cooling measures. In this study, we tested the hypothesis that external cooling measures reduce the responsivity of 5-HT2A receptors to excessive 5-HT efflux, which may be a possible mechanism underlying the treatment of serotonin syndrome. To test this, rat experiments were carried out in the standard and cool ambient temperature (Tamb) by administration of the 5-HT precursor 5-hydroxy-l-tryptophan combined with the monoamine oxidase inhibitor clorgyline. The first set of experiments was to assess severity of the syndromes by measuring body temperature responses. Consistent with the hypothesis, we found that the syndrome was malignant at the standard Tamb of 22°C but alleviated at 12 or 6°C, these results being similar to those in rats pre-treated with the 5-HT2A receptor antagonist ketanserin. The second set of experiments was to utilize microdialysis to determine the relationship between the syndrome severity and 5-HT levels at the above-mentioned Tamb. We found that excessive 5-HT efflux consisted of primary and secondary components through two distinct mechanisms. Furthermore, the secondary component efflux, which can be ascribed to 5-HT2A receptor activation, was proportionally reduced at the cool Tamb of 12 and 6°C. In conclusion, results of this study support the hypothesis that cooling Tamb reduces the functional activity of 5-HT2A receptors, thus alleviating the malignant syndrome.