Effects of 5-HT-moduline, a novel endogenous peptide, on serotonin releasein the prefrontal cortex of freely moving rats

Serotonin (5-HT)-moduline, a novel endogenous tetrapeptide (Leu-Ser-Ala-Leu ), is reported to interact with 5-HT1B receptors with a high affinity in a non-competitive manner. In this study, we aimed to clarify whether 5-HT-mod uline regulate 5-HT release in the rat prefrontal cortex (PFC) using in viv o microdialysis. Local perfusion of 5-HT-moduline (1, 10 and 100 muM) produ ced decreases in 5-HT release in a concentration-dependent manner. The 5-HT -moduline (10 muM)-induced inhibitory effects were prevented by pretreatmen t with the selective 5-HT1B/1D receptor antagonist, GR127935 (10 muM). GR12 7935 (10 muM) by itself did not affect the spontaneous 5-HT levels. These r esults indicate the possibility that 5-HT-moduline inhibits the 5-HT releas e via 5-HT1B receptors. 5-HT-moduline also influenced dopaminergic neuronal activities; 10 muM of 5-HT-moduline increased the extracellular dopamine ( DA) levels. Thus, 5-HT-moduline can modulate not only 5-HT but also DA rele ase in the rat PFC. These findings have been supported by the present resul ts that the selective 5-HT1B receptor agonist, CGS 12066A (10 muM) produced decreases in 5-HT release and increases in DA release in the PFC. Taken to gether, the present findings suggest that the functional modulation of 5-HT release by 5-HT-moduline, which may be mediated via 5-HT1B receptors locat ed on the nerve terminals, exists in vivo.