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The glutamatergic predominance in the excitatory-inhibitory balance is postulated to be involved in the pathogenesis of depression. Such imbalance may be induced by astrocyte ablation which reduces glutamate uptake and increases glutamate level in the synaptic cleft. In the present study, we tried to ascertain whether astroglial degeneration in the prefrontal cortex could serve as an animal model of depression and whether inhibition of glutamatergic transmission by the mGluR5 antagonist MTEP could have antidepressant potential. Astrocytic toxins l-or dl-alpha-aminoadipic acid (AAA), 100μg/2μl, were microinjected, bilaterally into the rat medial prefrontal cortex (PFC) on the first and second day of experiment. MTEP (10mg/kg) or imipramine (30mg/kg) were administered on the fifth day. Following administration of MTEP or imipramine the forced swim test (FST) was performed for assessment of depressive-like behavior. The brains were taken out for analysis on day eight. The astrocytic marker, glial fibrillary acidic protein (GFAP) was quantified in PFC by Western blot method and by stereological counting of immunohistochemically stained sections. Both l-AAA and dl-AAA induced a significant increase in immobility time in the FST. This effect was reversed by imipramine, which indicates depressive-like effects of these toxins. A significant decrease in GFAP (about 50%) was found after l-AAA. Both the behavioral and GFAP level changes were prevented by MTEP injection. The obtained results indicate that the degeneration of astrocytes in the PFC by l-AAA may be a useful animal model of depression and suggest antidepressant potential of MTEP.

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Earlier studies conducted by our group and by other authors indicated that metabotropic glutamatergic receptor (mGluR) ligands might have anxiolytic activity and that amygdalar neuropeptide Y (NPY) neurons were engaged in that effect. Apart from the amygdala, the hippocampus, another limbic structure, also seems to be engaged in regulation of anxiety. It is rich in mGluRs and contains numerous NPY interneurons. In the present study, we investigated the anxiolytic activity of group II and III mGluR agonists after injection into the hippocampus, and attempted to establish whether hippocampal NPY neurons and receptors were engaged in the observed effects. Male Wistar rats were bilaterally microinjected with the group II mGluR agonist (2S,, NPY, the Y1 receptor antagonist BIBO 3304, and the Y2 receptor antagonist BIIE 0246 into the CA1 or dentate area (DG). The effect of those compounds on anxiety was tested in the elevated plus-maze. Moreover, the effects of L-CCG-I and L-SOP on the expression of NPYmRNA in the hippocampus were studied using in situ hybridization method. It was found that a significant anxiolytic effect was induced by L-SOP injection into the CA1 region or by L-CCG-I injection into the DG. The former effect was inhibited by BIBO 3304, the latter by BIIE 0246. NPY itself showed antianxiety action after injection into both structures. In the CA1 area, the effect of NPY was prevented by BIBO 3304, whereas in the DG by BIIE 0246. Both the mGluR agonists L-CCG-I and L-SOP induced a potent increase in NPYmRNA expression in the DG region of the hippocampal formation. The obtained results indicate that group II and III mGluR agonists, L-CCG-I and L-SOP, as well as NPY display anxiolytic activity in the hippocampus, but act differently in the CA1 and DG. It was observed that group III mGluRs and Y1 receptors were engaged in the response in the CA1 area, whereas group II mGluRs and Y2 receptors played a pivotal role in the DG region.

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