Melatonin agonists modulate 5-HT2A receptor-mediated neurotransmission: behavioral and biochemical studies in the rat.

Interactions between melatonin and serotonin type 2A (5-HT2A) receptors in the regulation of the sleep-wakefulness cycle in the rat have been reported. We studied the acute effects of melatonin and related agonists on 5-HT2A neurotransmission as reflected in behavioral (head shake) and biochemical [phosphoinositide (PI) hydrolysis] responses to 5-HT2A receptor stimulation. Like 5-HT1A agonists and antidepressants, acute administration of melatonin and related agonists inhibited the 5-HT2A-mediated (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced head shake in a dose-dependent manner. Consistent with these behavioral findings, in vitro incubation of cortical slices with melatonin agonists robustly inhibited 5-HT2A receptor-mediated PI hydrolysis in a noncompetitive manner. 2-Iodomelatonin-induced reductions in 5-HT2A-stimulated PI hydrolysis were blocked by preincubation with the melatonin antagonist N-acetyltryptamine. Further, pretreatment of rats in vivo with melatonin and related agonists reduced the cortical PI hydrolysis response to the 5-HT2A agonist alpha methyl-5-HT but did not alter cortical 5-HT2A receptor density. The present data support an interaction between melatonin and 5-HT2A receptors in the central nervous system.