Involvement of NMDA receptor complex in the anxiolytic-like effects of chlordiazepoxide in mice

In the present study, we demonstrated that low, ineffective doses of N-methyl-d-aspartic acid (NMDA) receptor antagonists [competitive NMDA antagonist, CGP 37849, at 0.312 mg/kg intraperitoneally (i.p.), antagonist of the glycineB sites, L-701,324, at 2 mg/kg i.p., partial agonist of glycineB sites, d-cycloserine, at 2.5 mg/kg i.p.] administered jointly with an ineffective dose of the benzodiazepine, chlordiazepoxide (CDP, 2.5 mg/kg i.p.), significantly increased the percentage of time spent in the open arms of the elevated plus-maze (index of anxiolytic effect). Furthermore, CDP-induced anxiolytic-like activity (5 mg/kg i.p.) was antagonized by NMDA (75 mg/kg i.p.) and by an agonist of glycineB sites of the NMDA receptor complex, d-serine [100 nmol/mouse intracerebroventricularly (i.c.v.)]. The present study showed a positive interaction between γ-aminobutyric acid (GABA) and glutamate neurotransmission in the anxiolytic-like activity in the elevated plus-maze test in mice and this activity seems to particularly involve the NMDA receptors

Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist

1. Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and/or antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. Given the recent discovery of a selective and brain penetrable mGlu5 receptor antagonists, the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), i.e. the most potent compound described, was evaluated in established models of anxiety and depression. 2. Experiments were performed on male Wistar rats or male Albino Swiss or C57BL/6J mice. The anxiolytic-like effects of MPEP was tested in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. The antidepressant-like effect was estimated using the tail suspension test in mice and the behavioural despair test in rats. 3. MPEP (1 – 30 mg kg(−1)) induced anxiolytic-like effects in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. MPEP had no effect on locomotor activity or motor coordination. MPEP (1 – 20 mg kg(−1)) did shorten the immobility time in a tail suspension test in mice, however it was inactive in the behavioural despair test in rats. 4. These data suggest that selective mGlu5 receptor antagonists may play a role in the therapy of anxiety and/or depression, further studies are required to identify the sites and the mechanism of action of MPEP