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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

ABSTRACT

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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    • "Its pharmacological properties have been thoroughly described (Conn and Pin, 1997;Ferraguti and Shigemoto, 2006) and selective pharmacological agents targeting the mGluR5 have been developed (Gasparini et al., 1999;Anderson et al., 2002). Preclinical research with these agents suggests that this receptor is a candidate target for the treatment of MDD (Markou, 2007;Pilc et al., 2008;Palucha Poniewiera et al., 2013), Parkinson's disease (Marino et al., 2003;Johnson et al., 2009), schizophrenia (Conn et al., 2009;Herman et al., 2012), and addiction (Markou, 2007;Bird and Lawrence, 2009;Olive, 2009;Holmes et al., 2013;Pomierny-Chamiolo et al., 2014). The development of highly selective mGluR5 radiotracers such as[11C]ABP688 (Ametamey et al., 2006;Ametamey et al., 2007) has enabled the in vivo assessment of mGluR5 via positron emission tomography (PET) in humans (Terbeck et al., 2015). "
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    ABSTRACT: Background: Abundant evidence at the anatomical, electrophysiological, and molecular level implicates metabotropic glutamate receptors subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential which can be translated to the clinic. Methods: Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs MTEP and MPEP on paradigms with cocaine, ethanol, nicotine, and food in rats. Results: MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine, at doses equal to or higher than 1 mg/kg and 2.5 mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine but not food was reduced by MTEP and MPEP in the dose range 1-2 mg/kg and 2.5-3.2mg/kg, respectively. This dose range corresponds to approximately 50%-80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window. Conclusion: Altogether, this review suggests a therapeutic window for mGluR5 NAMs which can be translated to the treatment of substance-related and addictive disorders.
    Full-text · Article · Jan 2016 · The International Journal of Neuropsychopharmacology
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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.
    Full-text · Article · Nov 2013 · Pharmacological reports: PR

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