5-HYDROXYTRYPTAMINE-MODULINE, A NEW ENDOGENOUS CEREBRAL PEPTIDE, CONTROLS THE SEROTONERGIC ACTIVITY VIA ITS SPECIFIC INTERACTION WITH 5-HYDROXYTRYPTAMINE(1B 1D) RECEPTORS/

The serotonergic system controls the activity of neurotransmissions in volved in numerous physiological functions. It is also thought to be c rucially implicated in Various pathologies, including psychiatric diso rders such as depression, anxiety, and aggressiveness. The properties of 5-hydroxytryptamine (5-HT)-moduline, a novel endogenous peptide, ha ve been tested in vitro and in vivo. Binding studies have shown that t he peptide specifically interacts with 5-HT1B1D receptors via a noncom petitive mechanism corresponding to a high apparent affinity (EC(50) = 10(-10) M). The interaction was shown in rat and guinea pig brain tis sues and in cells transfected with either 5-HT1B or population of site s in mammalian brain (K-d = 0.4 nM in rat, K-d = 0.8 nM in guinea pig) as well as in transfected cells expressing the 5-HT1B or the 5-HT1D b eta receptors (K-d = 0.2 and 0.6 nM, respectively). Furthermore, the b inding is clearly specific of the LSAL sequence. Autoradiographic stud ies showed an heterogeneous brain distribution of this site. The inter action of 5-HT-moduline with the 5-HT1B/1D receptor corresponds to a d ecrease in the functional activity of the receptor (i.e., a decrease i n the inhibitory effect of a 5-HT1B agonist on the evoked release of [ H-3]5-HT from synaptosomal preparation). It was also shown that 5-HT-m oduline possess an in vivo effect in the social interaction test in mo use. Finally, ii was demonstrated that 5-HT-moduline was released from brain synaptosomal preparation by a K+/Ca2+-dependent mechanism. In c onclusion, 5-HT-moduline is a novel endogenous peptide regulating the serotonergic activity via a direct action at presynaptic 5-HT receptor . It may play an important role in the physiological mechanisms involv ing the serotonergic system, particularly in mechanisms corresponding to the elaboration of an appropriate response of the central nervous s ystem to a given stimulus.