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.

5-HT-moduline is an endogenous tetrapeptide, which acts specifically as an antagonist of 5-HT1B 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-HT1A (NAN 190, WAY 100635) and 5-HT1B receptor antagonist (methiothepine). Finally, we tried to potentiate non-active doses of HG1 with 5-HT1A (8-OHDPAT) and 5-HT1B 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-HT1A and 5-HT1B receptors.

Anxiolytic profile of HG1, a 5-HT-moduline antagonist, in three mouse models of anxiety.

HG1 is a new 5-HT-moduline antagonist which is itself an endogenous tetrapeptide specifically acting as an antagonist of 5-HT(1B) auto- and heteroreceptors. Blockade of endogenous 5-HT-moduline might provoke anxiolysis, so it could be a new therapeutic target in anxiety disorders. The aim of our study was to examine the effects of HG1 in three mouse models of anxiety: the four plates test (FPT), the black and white (B&W) model and the elevated plus maze (EPM). Male Swiss mice were intraperitoneally and acutely administered HG1 at the doses of 8, 16, 32 and 64 mg/kg. In these three tests, HG1 exhibited an anxiolytic profile similar to that of diazepam, the referential benzodiazepine compound, without affecting locomotor activity. In the three models used, HG1 was as efficient as benzodiazepine and may consequently exert its anxiolytic effects via the GABA-ergic system. We cannot exclude that it might also act through 5-HT receptors and rather have the profile of a selective serotonin reuptake inhibitor.

Interaction of lithium with 5-HT(1B) receptors in depressed unipolar patients treated with clomipramine and lithium versus clomipramine and placebo: preliminary results.

Lithium is commonly used in combination with antidepressant drugs as a treatment for refractory depression; less often, it is used in non-resistant depression. The aim of this study was to examine the interaction of lithium with 5-HT(1B) receptors in 10 non-resistant unipolar depressed patients treated with clomipramine+lithium (C+L) vs. clomipramine+placebo (C+P). A mediation of the serotonergic system has been proposed in the literature to explain the clinical effect of lithium. Indeed, in a previous study of healthy human blood platelets, we demonstrated the interaction of lithium with adenylate cyclase activity coupled to 5-HT(1B) receptors. The functional activity of these receptors was measured by studying the inhibitory effect of L694,247, a 5-HT(1B) receptor agonist, on the adenylate cyclase activity determined by the production of cAMP. Using the same technique in the present study, we found that lithium significantly reduced the inhibition of adenylate cyclase activity induced by 5-HT(1B) receptor activation. This result confirms the specific interaction of lithium with 5-HT(1B) receptors. Moreover, a correlation between the percentage of 5-HT(1B) receptor-dependent adenylate cyclase inhibition and the clinical benefit of lithium was established, suggesting 5-HT(1B) receptors may be a target for the therapeutic effect of lithium.