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

Abstract

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.

Keywords: 5-HT receptors; cyproheptadine; dopamine; malignant neuroleptic syndrome; serotonin syndrome.

Figure 1

The output from the POA is the result of the balance between TRPM2 and EP3 prostaglandin receptor mediated effects. TRMP2 activation by the endogenous intracellular agonist ADP-ribose increases the POA neuronal activity, i.e., GABAergic inhibition of downstream subaltern structures. Exogenous TRP M2 agonists (acetaminophen and possibly metamizole) have a similar effect. EP3 activation by the endogenous agonist PGE2 (dinoprostone) reduces POA neuronal activity i.e., reduces GABAergic inhibition (disinhibition) of downstream subaltern structures. NSAIDs by inhibiting cyclo-oxygenases reduce the availability of PGE2 and thus the activation of EP3. TRMP2 antagonists are not (yet) in clinical use.

Figure 2

The preoptic area (POA) of the anterior hypothalamus (area) sends GABAergic inhibitory efferent output to a number of partner and subaltern sites co-responsible for controlling body temperature. Glutamatergic neurons in the dorsal hypothalamic area (DHA) are under such inhibitory control. When disinhibited they activate the nucleus raphe pallidus (NRP) that subsequently activates sympathetic neurons. NRP is also under inhibitory dopaminergic control originating from the DHA. The nucleus raphe dorsalis (NRD; Sympatho-Motor Command System) is also tonically inhibited by POA. When disinhibited it allows serotoninergic activation of the nucleus raphe pallidus (NRP) with subsequent sympathetic activation. Direct activation of sympathetic neurons (bypassing the NRP) is also possible. An increase in sympathetic output favors heat generation (BAT catabolism) and reduces heat loss (peripheral vasoconstriction).

Figure 3

Assumed effect of centrally acting 5-HT1A agonists and antagonists on temperature.

Figure 4

Assumed effect of centrally acting 5-HT2 agonists and antagonists on temperature.

Figure 5

Assumed effect of centrally acting 5-HT3 agonists and antagonists on temperature.

Figure 6

Assumed effect of centrally acting 5-HT4 and 6 agonists and antagonists on temperature.

Figure 7

Assumed effect of centrally acting 5-HT7 agonists and antagonists on temperature.

Figure 8

Cyproheptadine (left panel) is an antagonist at most (probably all) serotonin receptor subtypes; while antagonism at even receptor subtypes is desirable (thumbs-up), such an effect at uneven receptors is probably less so (thumbs-down). Aripiprazole (right panel) is an antagonist at serotonin receptor subtypes 2A and 6 and a partial agonist at 1A (Emax ≈ 70% of 5-HT effect) and very weak agonist at 2C and 7 (Emax ≈ 10%).