The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review

http://dev.genetics.emory.edu/labs/docs/labdocs/warren/2003-trendinneuro-sw_1.pdf

The mGluR theory of fragile X mental retardation

The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.

Molecular Imaging with PET

The neurobiology and control of anxious states

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.




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.




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.




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.






British Journal of Pharmacology (2001) 132, 1423–1430; doi:10.1038/sj.bjp.0703923

/pdf/potential-anxiolytic-and-antidepressant-like-effects-of-mpep-3rpiorzvv5.pdf

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

Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats.

http://rabbit.if-pan.krakow.pl/~popikp/download/9790_klodzinska_neuropharm_1999.pdf

Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models.

Rationale: Substances acting as agonists of group II mGlu receptors with joint group I mGlu receptor antagonist effects, or group II mGlu receptors agonists, were shown to induce antianxiety-like effect in rats after intrahippocampal administration. Objective: The present study was undertaken to establish whether a more selective group I, II, III mGlu receptors agonists/antagonists induce anxiolytic-like effects after injection to the hippocampus. Methods: (S)-4-Carboxyphenylglycine [(S)-4CPG] and 7-(hydroxyimino)cyclopropan[b]chromen-1α-carboxylic ethyl ester (CPCCOEt), selective antagonists at group I mGlu receptors, or (+)1S, 2S, 5R, 6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and (2S, 1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), two selective agonists of group II mGlu receptors, as well as (1S, 2S, 4S, 5S)-2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I (ABHxD-I), an agonist at all three groups of mGlu receptors and L-serine-O-phosphate (L-SOP), an agonist at group III mGlu receptors, were used. All compounds were administered into the CA1 region of the dorsal hippocampus. The conflict drinking Vogel test in rats was used to estimate the anxiolytic-like effects of all the compounds. Results: After intrahippocampal administration, both selective group I mGlu receptors antagonists (S)-4CPG and CPCCOEt, as well as the selective agonists of group II mGlu receptors LY 354740 and L-CCG-I, and an agonist of group III mGlu receptors, L-SOP, induced anticonflict effects. Conclusion: Selective antagonists of group I mGlu receptors and agonists of group II and group III mGlu receptors exhibit anxiolytic-like activity in the conflict drinking test. It seems that the hippocampus may be one of the brain structures involved in the anticonflict effect of mGlu receptor agonists/antagonists.

The antianxiety-like effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors after intrahippocampal administration.

The glutamatergic system has received considerable attention over recent years as a potential target for anxiolytic drugs. In spite of the pronounced anxiolytic-like effects of competitive and non-competitive antagonists of NMDA receptors in animal models of anxiety, these substances can not be regarded as potential anxiolytic drugs, mainly due to their side-effect profiles (eg, ataxia, myorelaxation, impairment of learning and memory processes and psychotomimetic effects). Antagonists and partial agonists of the glycine, receptor inhibit function of the NMDA receptor complex and evoke in animals an anxiolytic-like response. Although data concerning anti-anxiety-like effects of glycine, receptor antagonists are not very promising, studies are underway to develop new, brain-penetrating agents devoid of side effects. Further developments are necessary to more fully elucidate the possible involvement of AMPA/kainate receptors in anxiety. The recent discovery of metabotropic glutamate receptors, which modulate the function of the glutamatergic system, offers new hope for discovery of a new generation of anxiolytics. MPEP, a highly selective, brain penetrable, noncompetitive mGlu5 receptor antagonist, evokes anxiolytic-like effects in several animal models of anxiety, remaining remarkably free of side effects. LY-354740, a selective brain-penetrable group II mGlu receptor agonist, evokes marked anxiolytic-like effects in animal models of anxiety. LY-354740 causes mild sedation in mice, does not disturb motor coordination and has no potential to cause dependence. Therefore mGlu receptor ligands may become the anxiolytics of the future, free from the side effects characteristic of benzodiazepines.

Aleksandra Kłodzińska

Papers

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

Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats.

Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models.

The antianxiety-like effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors after intrahippocampal administration.

Glutamate receptor ligands as anxiolytics.