Is the mGlu5 receptor a possible target for new antidepressant drugs?

Pharmacological reports: PR (Impact Factor: 1.93). 11/2013; 65(6):1506-1511. DOI: 10.1016/S1734-1140(13)71511-1
Source: PubMed


The current treatment of depression, based on conventional antidepressant drugs that influence monoaminergic systems, is not satisfactory, and innovative antidepressant drugs are still needed. The next generation of treatments needs to be more effective, fasteracting and better tolerated than currently used antidepressants. Agrowing body of evidence indicates that compounds that modulate the glutamatergic system may be a group of novel and mechanistically distinct agents for the treatment of depression. Both preclinical and clinical data show strong, rapid and sustained effects of the NMDA receptor antagonist ketamine in treatment-resistant depression. However, ketamine cannot be considered as a novel antidepressant drug because of its side-effects and abuse potential. Because glutamatergic transmission is controlled not only by ionotropic but also by metabotropic glutamate receptors, their involvement in the etiology and the therapy of depression has also been postulated. Here, we review data supporting the potential antidepressant activity of mGlu5 receptor antagonists as well as the involvement of mGlu5 receptors in the pathophysiology of depression.

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Available from: Andrzej Pilc, Feb 27, 2014
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    ABSTRACT: Although depression is a common disorder that is often resistant to pharmacotherapy, its pathophysiology has remained elusive. Since the early 1950s, when the first antidepressants were introduced, i.e., the non-selective MAO inhibitors and tricyclic drugs, a number of hypotheses describing ethiopathogenesis of depression and antidepressant drug action have been formulated. The Institute of Pharmacology, the Polish Academy of Sciences has performed experimental and clinical research focused on the pathophysiology of depression and the mechanisms of action of antidepressant drugs for over 40 years. Our results from this period have significantly contributed to understanding the complex mechanisms of antidepressant drug actions and new pathways that underpin the pathophysiology of depression. Most of these theories are based on the finding that the chronic administration of antidepressants leads to adaptive changes in pre- and post-synaptic monoaminergic and glutamatergic neurotransmission as well as to alterations in gene transcription and immune-inflammatory and neurotrophic factors, resulting in neuroplastic changes in the brain. Taking into account the functional interdependence of the neuronal, hormonal and immunologic systems, we propose neurodevelopmental and neuroimmune theories for affective disorders. Moreover, commonalities have been documented for the pathomechanisms of depression and neurodegenerative and metabolic disorders as well as drug dependence. The aim of this special issue is to briefly present the major research contributions and the new research directions of the Institute of Pharmacology, the Polish Academy of Sciences with respect to the neurobiology of affective disorders and the mechanisms of action of marketed and new putative antidepressant drugs.
    Pharmacological reports: PR 11/2013; 65(6):1441-1450. DOI:10.1016/S1734-1140(13)71504-4 · 1.93 Impact Factor
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    ABSTRACT: 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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