Behavioural Brain Research 238 (2013) 109–112 Contents lists available at SciVerse ScienceDirect Behavioural Brain Research j ourna l ho mepage: www.elsevier.com/locate/bbr Short communication A selective mGlu7 receptor antagonist MMPIP reversed antidepressant-like effects of AMN082 in rats Agnieszka Palucha-Poniewiera a,∗ , Andrzej Pilc a,b a Institute of Pharmacology, Polish Academy of Sciences, Sm˛ etna 12, 31-343 Kraków, Poland b Faculty of Public Health, Collegium Medicum, Jagiellonian University, Michalowskiego 12, 31-126 Kraków, Poland h i g h l i g h t s ◮ MMPIP did not induce antidepressant-like effects in the forced swim test in rats. ◮ MMPIP reversed antidepressant-like effects of AMN082 in rats. ◮ AMN082-induced decrease in locomotor activity of rats was not affected by MMPIP. a r t i c l e i n f o Article history: Received 20 August 2012 Received in revised form 5 October 2012 Accepted 7 October 2012 Available online 17 October 2012 Keywords: AMN082 Antidepressant Forced swim test mGlu7 receptor MMPIP a b s t r a c t Previous behavioural studies strongly indicated on potential antidepressant-like activity of mGlu7 posi- tive allosteric modulator, AMN082 (N,N ′ -dibenzhydrylethane-1,2-diamine dihydrochloride). However, the mechanism of action of this drug was not clear. Some recent data, showing possible off-target activities of AMN082 and its metabolites casted doubt on the role of mGlu7 receptor activation in the antidepressant-like activity of this compound. In the present study we used a selective mGlu7 receptor antagonist, MMPIP (6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one), to investigate the role of mGlu7 receptor blockade in the antidepressant action of AMN082 in the forced swim test (FST) in rats. We showed that MMPIP (10 mg/kg, i.p.) completely reversed AMN082 (8 mg/kg, i.p.)-induced behavioural effects, including decreased immobility time and increased swimming time, suggesting the crucial role of mGlu7 receptor activation in the antidepressant-like effects of AMN082 in the FST. On the other hand, our studies showed, that AMN082 (8 mg/kg, i.p.)-induced decrease in locomotor activity was not affected by MMPIP (10 mg/kg, i.p.), indicating on other, non-mGlu7 receptor- dependent mechanisms involved in changes in locomotor activity of rats after AMN082 administration. © 2012 Elsevier B.V. All rights reserved. 1. Introduction The glutamatergic system is the chief excitatory neurotrans- mitter system in the brain and is believed to be involved in the pathophysiology of several neurological and psychiatric disorders [8]. Nevertheless, except from few NMDA antagonists, such as: memantine, amantadine and some ampakines used as nootropic drugs (e.g. piracetam, aniracetam), the drugs acting via modula- tion of glutamatergic system are lacking. Currently, metabotropic glutamate receptor (mGlu) ligands are considered as very promis- ing future drugs. Their activity in animal models of several diseases, including psychiatric ones, has been described [1,2,11,14]. MGlu receptors form three groups of receptors: group I (mGlu1 and mGlu5 receptors), group II (mGlu2 and mGlu3 receptors) and ∗ Corresponding author. Tel.: +48 12 66 23 288; fax: +48 12 637 45 00. E-mail address: nfpaluch@cyf-kr.edu.pl (A. Palucha-Poniewiera). group III (mGlu4, mGlu6, mGlu7 and mGlu8 receptors) [3]. Most studies on potential therapeutic effects of mGlu ligands focussed on group I and II, not only because of their particular role, but also because of a large availability of both orthosteric and allosteric selective ligands, as pharmacological tools. The studies on group III mGlu receptors, including mGlu7 receptor, which seems to play the crucial role in the regulation of glutamatergic neurotransmission, have been hampered by the lack of selective and bioavailable lig- ands. However, the studies on mice with genetic ablation of mGlu7 receptors (mGlu7 KO mice) indicated on a potential role for mGlu7 receptor in the modulation of stress-related psychiatric disorders [4,7,9]. In 2005, first, selective, orally active mGlu7 positive allosteric modulator, AMN082, has been described [10] and began to be widely used as a pharmacological tool in behavioural pharmacol- ogy. Among many possible therapeutic applications of AMN082, antidepressant effects of the drug were proposed, based on the results of our behavioural studies, showing for the first time 0166-4328/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2012.10.004