On the mechanism of anti-hyperthermic effects of LY379268 and LY487379, group II mGlu receptors activators, in the stress-induced hyperthermia in singly housed mice

• Published in: Neuropharmacology 2012-01, Vol.62 (1), p.322-331
• Main Authors: Wierońska, J.M., Stachowicz, K., Brański, P., Pałucha-Poniewiera, A., Pilc, A.
• Format: Article
• Language: English
• Subjects: Amino Acids - therapeutic use; Analysis of Variance; Animals; Anxiety; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists - therapeutic use; Fever - drug therapy; Fever - etiology; Flumazenil - therapeutic use; GABA; GABA Antagonists - therapeutic use; GABA Modulators - therapeutic use; Group II mGlu receptors; LY379268; LY487379; Male; Mice; Phosphinic Acids - therapeutic use; Piperazines - therapeutic use; Propanolamines - therapeutic use; Pyridines - therapeutic use; Receptors, AMPA - metabolism; Ritanserin - therapeutic use; Serotonin; Serotonin Antagonists - therapeutic use; Social Isolation; Stress, Psychological - complications; Sulfonamides - therapeutic use
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2011.07.042

Earlier studies have demonstrated that the agonists of the mGlu2/3 receptors produced anxiolytic actions after peripheral administration. However, the mechanism of their action is still not clear. Therefore the aim of the present study was to specify the role of the GABAergic and serotonergic system in the mechanism of the anxiolytic activity of group II mGlu receptor activators by using the stress induced hyperthermia test (SIH) in singly housed mice. We used an orthosteric mGlu2/3 receptor agonist, LY379268, which induced anti-hyperthermic efficacy in the doses of 1–5mg/kg (73% of inhibition after a highest dose). The effect of the second ligand used, a mGlu2 receptor positive modulator (PAM), LY487379, was observed in a dose range of 0.5–5mg/kg and reached 53% of the inhibition. The blockade of GABAergic system by GABAA receptor antagonist flumazenil (10mg/kg) or GABAB receptor antagonist CGP55845 (10mg/kg), and the blockade of serotonergic system by 5-HT1A receptor antagonist WAY100635 (0.1 and 1mg/kg) or 5-HT2A/2C receptor antagonist ritanserin (0.5mg/kg) had no influence on the anti-hyperthermic effect induced by effective dose of LY379268. However, the action of the effective dose of LY487379 was enhanced when co-administered with flumazenil, WAY100635 (0.1mg/kg) and ritanserin. Similar results were observed for the subeffective dose of LY379268 (0.5mg/kg). WAY100635 in a dose of 1mg/kg did not induce any enhancing effect on the activity of compounds. Therefore, it seems that the antagonism towards GABAA receptors, presynaptic 5-HT1A and postsynaptic 5-HT2A/2C receptors is responsible for the phenomenon. This article is part of a Special Issue entitled ‘Anxiety and Depression’. ► The anti-hyperthermic efficacy of LY379268 is not dependent on GABA or serotonin. ► Blockade of GABAA receptor enhances anti-hyperhermic effect of LY487379 and LY379268. ► Blockade of 5HT receptors enhances anti-hyperhermic effect of LY487379 and LY379268.