Invited reviewmGlu2/3 and mGlu5 receptors: Potential targets for novel antidepressants
Highlights
► Agents acting on mGlu2/3 and mGlu5 receptors exhibit antidepressant effects. ► mGlu2/3 and mGlu5 receptor antagonists share neural mechanisms with ketamine. ► mGlu2/3 and mGlu5 receptors are useful targets for drug discovery for depression.
Introduction
The economic burden of mood disorders is immense, amounting to 100 billion USD in the US and 105 billion Euros in the EU (Greenberg et al., 2003; Andlin-Sobocki et al., 2005), making the mood disorders the most costly group out of all central nervous system (CNS) diseases. Depression represents also a social problem, with the lifetime prevalence rates of depression amounts to 16% in the USA (Kessler et al., 2003) and over 30 million people affected each year in the EU (Wittchen et al., 2011). With the advent of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) in the 1950s (Kuhn, 1958; Loomer et al., 1957), depression treatment was revolutionized, but remains virtually unchanged since then. Currently used drugs are barely adequate for depressive patients, particularly those diagnosed as treatment-resistant depression (TRD). The antidepressant drugs (ADs) are characterized by a slow onset of action (in double blind, placebo controlled trials, frequently at least 3–4 weeks of treatment are required to see mood improvement), poor efficacy (about 30–50% of patients respond to the initial regimen), and approximately 30% of patients are resistant to a series of treatments (Fekadu et al., 2009; Rosenzweig-Lipson et al., 2007; Rush et al., 2006; Trivedi et al., 2006). A wide range of adverse effects of ADs create also problems for depressed patients. Importantly, meta- analyses suggest that antidepressants are only marginally efficacious compared to placebos, especially at moderate levels of initial depression (Kirsch et al., 2008; Pigott et al., 2010). Needless to say, more effective drugs are needed. Our knowledge of the pathophysiology of depression is far from being complete, in spite of the over 50 years of intensive research, which for years focused almost exclusively on monoamines (Lapin and Oxenkrug, 1969; Schildkraut, 1965), for review see: Maj et al. (1984). Therefore, there is a strong need to search beyond monoaminergic systems to understand better the pathophysiology of depression on one hand and to find better drugs on the other. While numerous attempts to identify new targets for antidepressants failed at the clinical level, the glutamatergic system emerges as a particularly important target to develop new antidepressants and to understand the mechanisms of their antidepressant effects (Hashimoto, 2011; Leheste et al., 2008; Sanacora et al., 2012; Skolnick et al., 2009).
The antidepressant-like efficacy of ionotropic (NMDA) glutamate receptor antagonist was first demonstrated by Trullas and Skolnick (1990). Subsequently, functional changes in NMDA receptor complex following chronic antidepressant treatments were demonstrated (for review see (Skolnick et al., 2001, 2009)). After the demonstration that NMDA receptor antagonists had antidepressant-like actions in preclinical tests, an increasing number of clinical studies indicates that modulation of glutamatergic system might be a novel way to achieve rapid and sustained antidepressant effects in depression sufferers, including those diagnosed as TRD. The most promising data come from a series of studies on the antidepressant activity of an uncompetitive NMDA receptor antagonist, ketamine, which has a long history in analgesia and anesthesiology. The initial study by Berman et al. (2000) reported a significant efficiency of intravenously administered ketamine (0.5 mg/kg, 40 min) in a group of seven patients, who fulfilled DSM-IV criteria for major depression. The effect was strong [50% or greater decreases in Hamilton Depression Rating Scale (HDRS)]. A subsequent, randomized, placebo-controlled, double-blind crossover clinical study by Zarate et al. (2006) confirmed the robust and rapid antidepressant effects of ketamine (0.5 mg/kg) in the TRD patients. Considerable improvement was observed 2 h after ketamine infusion and continued to remain significant for 1 week. The antidepressant efficacy of ketamine was then reported in ECT-resistant major depressive disorder (MDD) (Ibrahim et al., 2011) and in treatment-resistant bipolar depression (Diazgranados et al., 2010). However, the number of very profound adverse effects precludes the routine use of ketamine (also a drug of abuse, known by such street names as “special K” which induces trance-like or hallucination states) to treat depression in the wider clinical practice.
Preskorn et al. (2008) demonstrated promising clinical data on the antidepressant effect of NR2B subunit specific NMDA receptor antagonist CP-101,606 (traxoprodil) in patients with TRD. This placebo controlled, double-blind study clearly showed that patients receiving CP-101,606 had a grater decrease in both the Montgomery-Asberg Depression Rating Scale (MADRS) and HDRS scores than placebo control subjects. Furthermore, it was shown that 78% of CP-101,606- treated patients maintained the response status for one week and 32% for 30 days after the infusion. Interestingly, the mechanism involved in the inhibitory action of CP-101,606 on the NMDA receptor differs from that of ketamine. CP-101,606 makes the receptor more sensitive to inhibition by protons, acting as endogenous negative modulators of NMDA receptor (Mott et al., 1998). One must be aware that both in the ketamine and traxoprodil studies a functional unblinding may have occurred due to the rapid onset of psychotomimetic effects induced by both drugs. On the other hand, the studies on memantine, which is a low-affinity, uncompetitive, open-channel NMDA receptor blocker, showed equivocal results. Although in animal models of depression memantine was found to exhibit antidepressant-like activity (Moryl et al., 1993; Rogoz et al., 2002), the clinical study by Zarate et al. (2006) showed no antidepressant effect in the patients with MDD. More promising results came from the study by Muhonen et al. (2008) who showed antidepressant effects in the patients with MDD and co-morbid alcohol dependence, however, lack of placebo group in this study, is a critical limitation of the value of the results.
Metabotropic glutamate (mGlu) receptors are a natural alternative to influence the glutamatergic system. These receptors are responsible for the modulation, but not for fast neuronal transmission (Nakanishi, 1992). The discovery of selective ligands of these receptors created new possibilities in the therapy of a variety of CNS diseases, including psychiatric disorders (Niswender and Conn, 2010; Wieronska and Pilc, 2009). At present, 8 subtypes of mGlu receptors have been identified, named from 1 to 8 (Pin et al., 1999; Pin and Duvoisin, 1995). mGlu receptors are currently divided into three different groups according to the DNA sequence homology, pharmacology profile and intracellular signal transduction pathways. Group I includes mGlu1 and mGlu5 subtypes, group II includes mGlu2 and mGlu3 receptors, and the group III includes mGlu4, mGlu6, mGlu7 and mGlu8 receptors (Conn and Pin, 1997; Pin and Duvoisin, 1995). A considerable number of papers have been published on mGlu receptors and depression/antidepressant activity (Hashimoto, 2011; Krystal et al., 2010; Palucha and Pilc, 2007; Pilc et al., 2008; Swanson et al., 2005; Wieronska and Pilc, 2009). In this review, we focus on mGlu5 and mGlu2/3 receptors because most of the available data concern these receptor types. With regard to mGlu2/3 receptor, because paradoxical results that both mGlu2/3 receptor agonists and antagonists show antidepressant effects have been reported, we discussed potential of mGlu2/3 receptor agonists and antagonists separately in this review and addressed the reason of this discrepancy in Summary and conclusions.
Section snippets
Preclinical evidence
Recent evidence showed that both selective mGlu2/3 receptor agonists and antagonists exhibit antidepressant-like activity in animal screening procedures that provide promising paths for the discovery of new and improved medications (Palucha and Pilc, 2007; Pilc et al., 2008). Among most mGlu receptor ligands, mGlu2 and mGlu3 receptor agonists seem to be the drugs with the promising therapeutic potential and a good safety profile. mGlu2 and mGlu3 receptors have been shown to be altered in animal
Preclinical evidence
Antidepressant-like effects of the orthosteric mGlu2/3 receptor antagonists, MGS0039 and LY341495, were first found in the rat FST and mouse tail-suspension test (TST) using normal animals (Chaki et al., 2004). More recently, studies have attempted to evaluate the effects of these drugs in paradigms implicated in the etiology of human depression. MGS0039 exhibited antidepressant effects in the learned helplessness test where treatment with MGS0039 for 7 days significantly reduced the number of
Preclinical and clinical evidence
The initial studies on potential antidepressant effects of mGlu5 receptor ligands demonstrated a marked antidepressant activity of the first nonselective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in the TST (Tatarczynska et al., 2001). Further studies confirmed antidepressant-like activity of MPEP not only in the TST (Belozertseva et al., 2007) but also in the FST in mice (Li et al., 2006). MPEP was also tested in the OB model of depression. It has been found, that
Summary and conclusions
Glutamatergic abnormalities have been suggested in pathophysiology of depression, based on changes in glutamate levels in blood and brain, and glutamate transmission in the brain regions of depressive patients by magnetic resonance spectroscopy (Sanacora et al., 2012). This hypothesis has recently been underpinned by the clinical evidence that agents acting on glutamatergic transmission such as ketamine, CP-101,606 and riluzole are effective for patients with MDD. In particular, robust and
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