Potential of 5-HT-moduline as a drug target for affective disorders

The serotonergic system is one of the aminergic neurotransmitter systems participating in the maintenance of homeostasis of the organism in mammals; accordingly, it regulates the activity of various cerebral functions to organize adapted responses of the brain to environmental stimuli. The regulatory activity of the serotonergic system itself is modulated by an endogenous mechanism based on an allosteric interaction involving a newly discovered peptide, 5-HT-moduline, and the 5-HT1B receptor which, as an autoreceptor, controls the release of 5-HT from serotonergic neuron terminals. 5-HT-moduline specifically interacts with 5-HT1B receptors at nanomolar concentrations resulting in the desensitization of the receptor. As 5-HT1B autoreceptors have an inhibitory effect on the release of 5-HT, 5-HT-moduline ultimately increases its release. The peptide is characterized by several criteria which correspond to those of a neurotransmitter, strongly suggesting that 5-HT-moduline is a novel neuropeptide locally controlling serotonergic activity. 5-HT-moduline is released in various parts of the brain, particularly under conditions of stress; moreover, its deactivation by specific antibodies in mice induces changes in the behavior of the animal. These results strongly suggest that the peptide may play a role in the physiopathology of central nervous system disorders in mammals, particularly in conditions related to stress and anxiety. Furthermore, the fact that 5-HT-moduline increases the release of 5-HT suggests that synthetic drugs which recognize the 5-HT-moduline binding site on 5-HT1B receptors and mimic the effect of the peptide, may have antidepressant properties by increasing the release of 5-HT.