Behavioural Brain Research 158 (2005) 339–348 Research report Role of GABA-ergic and serotonergic systems in the anxiolytic-like mechanism of action of a 5-HT-moduline antagonist in the mouse elevated plus maze Florence Cl´ enet a , Martine Hasco¨ et a , Gilles Fillion a , Herv´ e Galons b , Michel Bourin a,∗ a EA 3256, Neurobiologie de l’anxi´ et´ eetdelad´ epression, Facult´ edeM´ edecine, BP 53508, 1 rue Gaston Veil, 44035 Nantes Cedex 01, France b Facult´ e des Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, 75006 Paris, France Received 21 June 2004; accepted 13 September 2004 Abstract 5-HT-moduline is an endogenous tetrapeptide, which acts specifically as an antagonist of 5-HT 1B auto- and heteroreceptors. HG1 is an ethyl arylmethyloxypiperidine acetate and an antagonist of 5-HT-moduline, which has no 5-HT-moduline agonist effect. In a pilot study, HG1 has demonstrated an anxiolytic-like profile in three mouse models of anxiety (elevated plus maze, light/dark, four plates). The aim of our study was to examine the mechanism of the anxiolytic-like effects of HG1 in the mouse elevated plus maze. Male Swiss mice were acutely administered HG1 at active doses in association with GABA antagonists such as flumazenil, bicuculline and picrotoxine, then, with 5-HT 1A (NAN 190, WAY 100635) and 5-HT 1B receptor antagonist (methiothepine). Finally, we tried to potentiate non-active doses of HG1 with 5-HT 1A (8-OHDPAT) and 5-HT 1B receptor agonists (anpirtoline) in the mouse elevated plus maze. Regarding GABA antagonists, only flumazenil antagonised active doses of HG1 in an incomplete manner. Moreover, non-active doses of HG1 were potentiated by low doses of WAY 100635 and by anpirtoline but not by 8-OHDPAT. Finally, the anxiolytic-like effects of HG1 at active doses were antagonised by all serotonergic antagonists (WAY 100635 at higher dose, NAN 190 and methiothepin). HG1 mechanism of action in the mouse elevated plus maze seems to associate a GABA-ergic component exerting a limited regulation of 5-HT neuronal activity and a major serotonergic component, which seems to implicate presynaptic 5-HT 1A and 5-HT 1B receptors. © 2004 Elsevier B.V. All rights reserved. Keywords: Serotonin (5-HT); 5-HT-moduline; GABA A receptor; 5-HT 1A receptor; 5-HT 1B receptor; Mouse elevated plus maze (EPM) 1. Introduction 5-HT 1A somatodendritic autoreceptors inhibit the electric activity of serotonergic neurons in the dorsal raphe and their activation decreases 5-HT release in brain areas such as the striatum, amygdala and hippocampus [2,20,35,30]. 5-HT 1B presynaptic receptors decrease 5-HT release in the cortex, hippocampus, cerebellum and hypothalamus in vitro and in vivo in the rat. These receptors have also a function of het- ∗ Corresponding author. Tel.: +33 2 40 41 28 53; fax: +33 2 40 41 28 56. E-mail address: mbourin@sante.univ-nantes.fr (M. Bourin). eroreceptor whose activation, in the rat cerebellum, decreases GABA release [21]. Moreover, they modulate the release of acetylcholine in the hippocampus [28], glutamate in the cerebellum [32] and dopamine in the striatum [34]. 5-HT- moduline, an endogenous ligand has been found to modulate 5-HT 1B receptors. In fact, 5-HT-moduline is an endogenous tetrapeptide (Leu-Ser-Ala-Leu), isolated and characterised by Fillion and Fillion [15], which specifically interacts in a non compet- itive manner with the binding of [ 3 H]5-HT to 5-HT 1B/1D . Biochemical studies have suggested that the 5-HT-moduline binding site is different from that of 5-HT [27,33]. An 0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2004.09.015