Hyperthermia and Serotonin: The Quest for a "Better Cyproheptadine".

Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant mechanisms of adjusting the body temperature to the value set by the internal thermostat exist. The neural circuitry of temperature control and the neurotransmitters involved are reviewed. The GABAergic inhibitory output from the brain thermostat in the preoptic area POA to subaltern neural circuitry of temperature control (Nucleus Raphe Dorsalis and Nucleus Raphe Pallidus) is a function of the balance between the (opposite) effects mediated by the transient receptor potential receptor TRPM2 and EP3 prostaglandin receptors. Activation of TRPM2-expressing neurons in POA favors hypothermia, while inhibition has the opposite effect. Conversely, EP3 receptors induce elevation in body temperature. Activation of EP3-expressing neurons in POA results in hyperthermia, while inhibition has the opposite effect. Agonists at TRPM2 and/or antagonists at EP3 could be beneficial in hyperthermia control. Activity of the neural circuitry of temperature control is modulated by a variety of 5-HT receptors. Based on the theoretical model presented the "ideal" antidote against serotonin syndrome hyperthermia appears to be an antagonist at the 5-HT receptor subtypes 2, 4 and 6 and an agonist at the receptor subtypes 1, 3 and 7. Very broadly speaking, such a profile translates in a sympatholytic effect. While a compound with such an ideal profile is presently not available, better matches than the conventional antidote cyproheptadine (used off-label in severe serotonin syndrome cases) appear to be possible and need to be identified.