Anxiolytic-like effects of group III mGlu receptor ligands in the hippocampus involve GABAA signaling

Recent literature data and the results of our earlier pharmacological studies, have provided evidence that antagonists of group I metabotropic glutamate receptors (mGluRs) and agonists of group II mGluRs show anxiolytic-like properties in preclinical and clinical studies. Out of all glutamate receptors, the role of group III mGluRs in anxiety-like states is the least investigated because of the lack of specific pharmacological tools, moreover all group III receptor ligands synthesized so far are not systemically active, so they have to be administered centrally. In the present study, we investigated the anxiolytic-like activity of group III mGlu receptor ligands including a nonselective group III mGlu receptor agonist (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), group III mGlu receptor antagonist, (RS)-alpha -cyclopropyl-4-phosphonophenylglycine (CPPG) and a positive allosteric modulator of mGluR4 (-)-N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). The Vogel conflict drinking test in rats was used to test the anxiolytic-like effects. The hippocampus was chosen as a site of the injection of drugs, as this brain regions is involved in the regulation of anxiety-related behavior. Intrahippocampal injections (CA1 region of the hippocampus) of PHCCC (12 nmol) but not of CPPG (75 nmol ) produced an anxiolytic-like response, moreover, the effect of PHCCC was totally blocked by CPPG. The anxiolytic-like effects of ACPT-I (7.5 nmol) or PHCCC (12 nmol) were significantly attenuated by flumazenil (10 mg/kg), indicating an involvement of GABAergic system in the anxiolytic-like response.     

Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent

Literature data have provided evidence that antagonists of group I metabotropic glutamate receptors (mGluRs) and agonists of group II/III mGluRs show anxiolytic-like properties in preclinical studies. However data reporting anxiolytic-like action of group III mGlu receptor antagonists were also published. In the present paper we investigated the anxiolytic-like activity of the group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). To examine its anxiolytic-like effects, the basolateral amygdala was chosen as an injection site, as this brain region is involved in the regulation of anxiety-related behavior. To detect anxiolytic-like activity, the Vogel conflict-drinking test in rats was used. Intra-amygdalar injections of CPPG exhibited dose-dependent, potent anxiolytic-like action at a dose of 75 nmol, which was blocked by a concomitant administration of the group III mGlu receptor agonist CI (S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) at a dose of 7.5 nmol. The benzodiazepine receptor antagonist flumazenil (given intraperitoneally, 10 mg/kg) did not change the anxiolytic-like effect of CPPG, but that effect was abolished by the non-selective antagonist of 5-HT receptors metergoline and the antagonist of 5-HT2A/C receptors ritanserin (both given intraperitoneally at doses of 2 and 0.5 mg/kg, respectively). These findings suggest that the blockade of group III mGlu receptors in the amygdala is responsible for anxiolysis and that serotonergic, but not the benzodiazepine recognition site of the GABA-ergic system are involved in the anxiolytic-like response induced by group III mGlu antagonist.     

Anxiolytic- and antidepressant-like effects of group III metabotropic glutamate agonist (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) in rats

We examined the anxiolytic-like activity of (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) using the Vogel conflict drinking test, while antidepressant-like effects of this compound were evaluated using Porsolt's test. ACPT-I, a selective group III mGlu receptor agonist, produced a dose-dependent anticonflict effect after intrahippocampal injections and antidepressant-like effect in rats after intraventricular injections. These data suggest that selective group III mGlu receptor agonists may become a new class of anxiolytics and/or antidepressants.     

Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.     

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

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. In view of the recent discovery of anxiolytic- or antidepressant-like effects of acute injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective and brain penetrable mGlu5 receptor antagonist, we designed the present study to examine anxiolytic- and/or antidepressant-like effects of multiple administrations of this drug. The anxiolytic-like effects of MPEP were evaluated in rats using the conflict drinking test. The antidepressant-like effect was estimated using the rat olfactory bulbectomy model of depression. Seven subsequent injections of MPEP (1 mg/kg) significantly (by 320%) increased the number of shocks accepted during the experimental session in the Vogel test. MPEP given once daily at a dose of 10 mg/kg, restored the learning deficit of bulbectomized rats after 14 days of treatment, remaining without any effect in the sham-operated animals. N-methyl-D-aspartic acid (NMDA)-induced convulsions in mice were not affected by a single injection of MPEP (30 mg/kg) indicating that at this dose MPEP did not block NMDA receptors. The results indicate that the prolonged blockade of mGlu5 receptors exerts anxiolytic- and antidepressant-like effects in rats. No tolerance to anxiolytic-like action occurs. The previously mentioned results further indicate that antagonists of group I mGlu receptors may play a role in the therapy of both anxiety and depression.     

Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease

Background and purpose:

Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson''s disease (PD). This study aimed to establish whether activation of pre-synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD.

Experimental approach:

Broad-spectrum group III mGlu receptor agonists, O-phospho-l-serine (l-SOP) and l-2-amino-4-phosphonobutyrate (l-AP4), were assessed for their ability to inhibit KCl-evoked [³H]-d-aspartate release in rat nigral prisms or inhibit KCl-evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine-treated rats was assessed following intranigral injection of l-SOP and l-AP4. Finally, the neuroprotective effect of 7 days'' supra-nigral treatment with l-AP4 was examined in 6-hydroxydopamine (6-OHDA)-lesioned rats.

Key results:

l-SOP and l-AP4 inhibited [³H]-d-aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG). l-SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l-SOP and l-AP4 into the SNpr reversed reserpine-induced akinesia. Following administration above the SNpc, l-AP4 provided neurochemical, histological and functional protection against 6-OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects.

Conclusions and implications:

These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects.     

Actions of LY341495 on metabotropic glutamate receptor-mediated responses in the neonatal rat spinal cord

1. The group II metabotropic glutamate (mGlu) receptor antagonist (2S,1'S,2'S)-2-(2-carboxycyclopropyl)-2-(9H-xanthen-9-yl)glycine (LY341495) also has activity at group I and III mGlu receptors at higher concentrations and can be used to discriminate between mGlu receptor subtypes. We report the antagonist action of LY341495 on glutamate receptors expressed in the neonatal rat spinal cord preparation and the use of this antagonist to investigate the group III mGlu receptor subtypes responsible for mediating the depression of synaptic transmission in the spinal cord mediated by the group III mGlu receptor agonists (S)-2-amino-4-phosphonobutanoic acid ((S)-AP4) and (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-I). 2. LY341495 antagonised mGlu receptor agonist-induced responses in the spinal cord with a rank order of potency of group II > group III > group I, which is the same as that observed in human cloned mGlu receptor cell lines. Antagonism of group II and III mGlu receptor-mediated effects were time dependent when low-nanomolar concentrations of LY341495 were used. Although the rank order of potency of LY341495 was the same on native rat and cloned human mGlu receptors, there was a compression in the selectivity between group II and III mGlu receptors, expressed in the spinal cord. 3. In agreement with a previous study on cloned ionotropic glutamate receptors 100 microM LY341495 had little or no effect on N-methyl-D-aspartate, (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid or kainate receptor-mediated responses on motoneurones. 4. LY341495 exhibited low-nanomolar potency antagonist activity against (S)-AP4 and ACPT-I suggesting that these agonists are activating predominantly mGlu8 and that mGlu4 receptors do not play a role in modulating synaptic transmission in the pathways stimulated in the experiments described here.     

Differential roles of mGlu8 receptors in the regulation of glutamate and gamma-aminobutyric acid release at periaqueductal grey level

We investigated the role of group III metabotropic glutamate (mGlu) receptors on glutamate and GABA releases at the periaqueductal grey (PAG) level by using in vivo microdialysis in rats. Intra-PAG perfusion of either L-(+)-2-amino-4-phosphonobutyric acid (L-AP4, 100-300 microM), (RS)-4-phosphonophenylglycine ((RS)-PPG, 100-300 microM) selective agonists of group III mGlu receptors, or (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG, 50-100 microM), a selective agonist of mGlu8 receptor, increased glutamate and decreased GABA extracellular concentrations. (RS)-alpha-methylserine-O-phosphate (MSOP, 0.5 mM), a selective group III receptor antagonist, perfused in combination with (S)-3,4-DCPG, L-AP4 or (RS)-PPG, antagonised the effects induced by these agonists on both extracellular glutamate and GABA values. alpha-Methyl-3-methyl-4-phosphonophenylglycine (UBP1112, 300 microM), a group III mGlu receptor antagonist, perfused in combination with (RS)-PPG or (S)-3,4-DCPG, antagonised the effects induced by these agonists. Intra-PAG perfusion with forskolin (100 microM), an activator of adenylate cyclase, increased dialysate glutamate and GABA levels. Moreover, intra-PAG perfusion with N-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) (100 microM), a protein kinase (PKA) inhibitor, abolished the effect of (S)-3,4-DCPG on both glutamate and GABA releases. H-89, per se, did not modify glutamate release but reduced extracellular GABA value at the higher dosage used (200 microM). These data suggest that group III mGlu receptors in the PAG modulate the releases of glutamate and GABA conversely. In particular, both the facilitation of glutamate and the inhibition of GABA releases require the participation of coupling to adenylate cyclase and the subsequent activation of the PKA pathway.     

Pharmacological profiles of the metabotropic glutamate receptor ligands

Metabotropic glutamate receptors (mGluRs) are a family of G-protein coupled receptors that are expressed in the central and peripheral nervous systems. The purpose of this study was to compare the ligand binding selectivity profiles of the mGluR agonist [(3)H]L-AP4 and the novel radiolabeled phenylglycine antagonist [(3)H]CPPG at all eight rat mGluR subtypes expressed in transfected human embryonic kidney cells. At a concentration of 30 nM [(3)H]L-AP4, no specific binding was detected in membranes expressing the group I receptors mGluR1a or mGluR5a, or in membranes expressing the group II mGluRs, mGluR2 and mGluR3. Among the group III mGluRs, specific [(3)H]L-AP4 binding was detected in cells expressing mGluR4a and mGluR8a but not in cells expressing mGluR6 or mGluR7a. The binding of [(3)H]CPPG showed an exceptional pattern of selectivity amongst the mGluR subtypes; at a concentration of 20 nM [(3)H]CPPG, a high level of specific binding was seen in membranes containing mGluR8a but not in any of the other mGluR subtypes. The affinity constant (K(D)) calculated for [(3)H]CPPG binding to mGluR8a was 183 nM. In competition experiments, the phosphono-substituted phenylglycine congeners including MPPG, (RS)-PPG, and unlabeled CPPG were the most potent inhibitors of [(3)H]CPPG binding while non-phosphonated compounds such as L-glutamate and MCPG were substantially less potent. These results demonstrate that [(3)H]L-AP4 and [(3)H]CPPG can be used as probes to selectively label group III mGluRs and that CPPG and related phenylglycine derivatives are useful for studying differences in the ligand recognition sites of highly homologous mGluRs.     

On the role of metabotropic glutamate receptors in the mechanisms of action of antidepressants

Most conventional antidepressant drugs influence serotoninergic, adrenergic, and/or dopaminergic systems, increasing serotonin, norepinephrine and dopamine synaptic availability. More recently attention has focused on glutamatergic system. Both preclinical and clinical studies, showing antidepressant-like actions of compounds which reduce transmission at N-methyl-D-aspartate (NMDA) receptors, indicate possible involvement of glutamatergic system in the etiology of depression. Since glutamatergic transmission is controlled not only by ionotropic but also by metabotropic glutamate receptors (mGluR), their involvement in the etiology and the therapy of depression was also postulated. Recent studies, showing that antidepressant treatment may influence mGlu receptors, together with the findings that group I mGluR antagonists, may possess antidepressant-like action, support this hypothesis.     

Mood disorders: regulation by metabotropic glutamate receptors

Medicinal therapies for mood disorders neither fully serve the efficacy needs of patients nor are they free of side-effect issues. Although monoamine-based therapies are the primary current treatment approaches, both preclinical and clinical findings have implicated the excitatory neurotransmitter glutamate in the pathogenesis of major depressive disorders. The present commentary focuses on the metabotropic glutamate receptors and their relationship to mood disorders. Metabotropic glutamate (mGlu) receptors regulate glutamate transmission by altering the release of neurotransmitter and/or modulating the post-synaptic responses to glutamate. Convergent biochemical, pharmacological, behavioral, and clinical data will be reviewed that establish glutamatergic neurotransmission via mGlu receptors as a biologically relevant process in the regulation of mood and that these receptors may serve as novel targets for the discovery of small molecule modulators with unique antidepressant properties. Specifically, compounds that antagonize mGlu2, mGlu3, and/or mGlu5 receptors (e.g. LY341495, MGS0039, MPEP, MTEP) exhibit biochemical effects indicative of antidepressant effects as well as in vivo activity in animal models predictive of antidepressant efficacy. Both preclinical and clinical data have previously been presented to define NMDA and AMPA receptors as important targets for the modulation of major depression. In the present review, we present a model suggesting how the interplay of glutamate at the mGlu and at the ionotropic AMPA and NMDA receptors might account for the antidepressant-like effects of glutamatergic- and monoaminergic-based drugs affecting mood in patients. The current data lead to the hypothesis that mGlu-based compounds and conventional antidepressants impact a network of interactive effects that converge upon a down regulation of NMDA receptor function and an enhancement in AMPA receptor signaling.     

Functional interaction between adenosine A2A and group III metabotropic glutamate receptors to reduce parkinsonian symptoms in rats

Non-dopaminergic drugs acting either on adenosine A2A or metabotropic glutamate (mGlu) receptors reduce motor impairment in animal models of Parkinson's disease (PD), suggesting a possible functional interaction between these receptors to regulate basal ganglia function. The present study therefore tested the behavioural effects of compounds acting selectively on A2A or on specific mGlu receptor subtypes, alone or in combination, in rodent models of PD. Acute administration of the adenosine A2A receptor antagonists CSC or MSX-3 at the highest doses tested (5 and 1.25mg/kg, respectively) significantly reduces haloperidol-induced catalepsy. Furthermore, the anticataleptic effect of MSX-3 was enhanced by a 3-week treatment. Acute administration of the selective group III mGlu agonist ACPT-I produces potent anticataleptic effects and prolongs time on rotarod of 6-OHDA-lesioned rats. In contrast, acute or chronic administration of MPEP (mGlu5 receptor antagonist) has no anticataleptic action. Furthermore, the acute co-administration of ACPT-I 1mg/kg, but not 5mg/kg, with CSC markedly reduces catalepsy. Opposite effects are observed after a 3-week co-administration. The co-administration of ACPT-I with MSX-3 has anticataleptic effects both after acute or chronic treatment. In contrast, acute combination of subthreshold doses of CSC and MPEP has no effect. After a 3-week treatment, however, the combination of CSC and MPEP was found to reduce haloperidol-induced catalepsy. Altogether, these results show for the first time that systemic activation of group III mGlu receptors with ACPT-I provides benefits in parkinsonian rats and underlie a possible interaction with A2A receptors to regulate basal ganglia motor function.     

Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia?

Agonists for mGlu2/3 receptors decrease the evoked release of glutamate at certain (ie. forebrain / limbic) glutamatergic synapses, indicating that the functional role of mGlu2 and/or mGlu3 receptors is to suppress glutamate excitations. This offers a mechanism for dampening glutamate excitation under pathological states resulting from excessive glutamate release. Based, in part, on the psychotomimetic actions of phencyclidine (PCP)- like drugs, excessive or pathological glutamate release has been implicated in a number of clinical conditions including psychosis. With this in mind, the pharmacology of multiple mGlu2/3 receptor agonists have been investigated in PCP treated rats. Agonists for mGlu2/3 receptors such as LY354740 and LY379268 have been shown to block certain behavioral responses to PCP in rats. The effects of mGlu2/3 agonists on PCP-induced behaviors are blocked by a low doses of a selective mGlu2/3 receptor antagonist, indicating that these actions are mediated via mGlu2/3 receptors. In addition, mGlu2/3 agonists potently suppress glutamate release in rat prefrontal cortex, as reflected by excitatory post-synaptic potentials (EPSPs) induced by serotonin (5-HT) acting on 5HT(2A) receptors. These actions of LY354740 and LY379268 are also blocked by a selective mGlu2/3 antagonist. Atypical antipsychotic drugs such as clozapine also suppress 5-HT-induced EPSPs in this brain region, thus suggesting a common pathway for the actions of atypical antipsychotic drugs and mGlu2/3 receptor agonists. As glutamatergic dysfunction has been implicated in psychotic states and possibly in the etiology of schizophrenia, clinical studies with mGlu2/3 agonists may be warranted to further explore the validity of the glutamatergic hypothesis of schizophrenia.     

Are compounds acting at metabotropic glutamate receptors the answer to treating depression?

Numerous studies over the last few years have suggested that modulating the glutamatergic system may be an efficient method to achieve an antidepressant effect. Data suggest that metabotropic glutamate receptors (mGlu receptors), related to long-term, modulatory effects on glutamatergic neurotransmission, may be a good target for the development of new, effective and safe therapeutic drugs to treat several CNS disorders including depression and anxiety. Several potent, selective and systemically active orthosteric and allosteric ligands of specific mGlu receptor subtypes have been discovered and these have been tested as potential antidepressants in models of depression in rodents. The mGluR5 antagonists and group II mGlu receptor antagonists seem to be the most promising compounds with potential antidepressant-like activity; however, the efficacy of mGlu receptor ligands in the clinical setting is still an unanswered question.     

Na+/H+ exchanger-1: a link with atherogenesis?

Numerous studies over the last few years have suggested that modulating the glutamatergic system may be an efficient method to achieve an antidepressant effect. Data suggest that metabotropic glutamate receptors (mGlu receptors), related to long-term, modulatory effects on glutamatergic neurotransmission, may be a good target for the development of new, effective and safe therapeutic drugs to treat several CNS disorders including depression and anxiety. Several potent, selective and systemically active orthosteric and allosteric ligands of specific mGlu receptor subtypes have been discovered and these have been tested as potential antidepressants in models of depression in rodents. The mGluR5 antagonists and group II mGlu receptor antagonists seem to be the most promising compounds with potential antidepressant-like activity; however, the efficacy of mGlu receptor ligands in the clinical setting is still an unanswered question.     

Anxiolytic action of group II and III metabotropic glutamate receptors agonists involves neuropeptide Y in the amygdala

Several lines of evidence indicate that activation of group II and III metabotropic glutamate (mGlu) receptors produces anxiolytic-like effects in rodents. On the other hand neuropeptide Y (NPY) induces an anxiolytic effect in rats after intraventricular or intraamygdalar administration. Therefore, in the present study we investigated whether the anxiolytic action of (2S,3S,4S)-(carboxycyclopropyl)glycine (L-CCG-I), an mGlu2/3 receptor agonist, and (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-1), an mGluR4/6/7/8 receptor agonist, was mediated by a mechanism involving NPY receptor. In behavioral studies, the anxiolytic activity of L-CCG-I (10 microg/0.5 microl/site) and ACPT-1 (1.5 microg/0.5 microl/site) was examined using plus-maze tests. The Y1 receptor antagonist BIBO 3304 was given at a dose of 128 ng/0.5 microl/site. All the compounds tested were injected bilaterally into the amygdala, BIBO 40 min and mGluR agonists 30 min before the test. It was found that the anxiolytic effects of mGluR agonists were abolished by BIBO 3304 {((R)-N-[[4-(aminocarbonylaminomethyl) phenyl] methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate)3304} administration. Immunohistochemical studies showed a moderate density of mGlu2/3 receptor immunoreactivity (IR) in the amygdala. The effect of L-CCG-I and ACPT-1 on NPY expression in the amygdala was studied using immunohistochemistry (IH), while NPYmRNA expression was studied using in situ hybrydization. We showed a diminution in NPY-IR after L-CCG-I administration and decrease in NPYmRNA expression after both L-CCG-I and ACPT-1 treatment, to about 77% (IH) or 32-41% (mRNA) of the control level 18 h after injection of these mGluR agonists. Our results indicate that the anxiolytic action of both compounds is conveyed by NPY neurons with the involvement of Y1 receptors in the amygdala, and that NPY neurons seem to be regulated by the glutamatergic system.     

Metabotropic glutamate receptors: potential drug targets for the treatment of schizophrenia

Schizophrenia is a debilitating chronic psychiatric illness affecting 1% of the population. The cardinal features of schizophrenia are positive symptoms (thought disorder, hallucinations, catatonic behavior), negative symptoms (social withdrawal, anhedonia, apathy) and cognitive impairment. Although progress in elucidating the aetiology of schizophrenia has been slow, new insights on the neurochemical and neurophysiological mechanisms underlying the pathophysiology of this illness are beginning to emerge. The glutamate/N-methyl-D-aspartate (NMDA) hypofunction hypothesis of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine induces psychosis in humans; moreover, decreased levels of glutamate and changes in several markers of glutamatergic function occur in schizophrenic brain. Administration of PCP or ketamine to rodents elicits an increase in locomotion and stereotypy accompanied by an increase in glutamate efflux in several brain regions. Systemic administration of group II metabotropic glutamate (mGlu) receptor agonists suppresses PCP-induced behavioral effects and the increase in glutamate efflux. Activation of group II mGlu receptors (mGlu2 and mGlu3) decreases glutamate release from presynaptic nerve terminals, suggesting that group II mGlu receptor agonists may be beneficial in the treatment of schizophrenia. In addition, pharmacological manipulations that enhance NMDA function may be efficacious antipsychotics. Selective activation of mGlu5 receptors significantly potentiates NMDA-induced responses, supporting this novel approach for the treatment of schizophrenia. The glutamate hypothesis of schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the antipsychotic potential of these novel therapeutics. This review will discuss recent progress in elucidating the pharmacology and function of group II mGlu and mGlu5 receptors in the context of current hypotheses on the pathophysiology of schizophrenia and the need for new and better antipsychotics.     

Activation of the mGlu7 receptor elicits antidepressant-like effects in mice

Rationale Broad evidence indicates that modulation of the glutamatergic system could be an efficient way to achieve antidepressant activity. Metabotropic glutamate receptor (mGlu receptor) ligands seem to be promising agents to treat several central nervous system disorders, including psychiatric ones. Objectives The aim of our study was to investigate potential antidepressant-like activity of the first, selective, and bio-available mGlu7 receptor agonist, AMN082 (N,N′-dibenzyhydryl-ethane-1,2-diamine dihydrochloride), in wild-type (WT) and mGlu7 receptor knock-out (KO) mice. Materials and methods The forced swim test (FST) and the tail suspension test (TST) in mice were used to assess antidepressant-like activity of AMN082. Results We found that AMN082, administered IP, induced a dose-dependent decrease in the immobility time of WT animals in the FST and TST, suggesting antidepressant-like potency of an mGlu7 receptor agonist. Moreover, AMN082 did not change the behaviour of mGlu7 receptor KO mice compared to WT littermates in the TST, while imipramine, used as a reference control, significantly reduced their immobility, indicating an mGlu7 receptor-dependent mechanism of the antidepressant-like activity of AMN082. However, at high doses, AMN082 significantly decreased spontaneous locomotor activity of both mGlu7 receptor KO mice and WT control animals, suggesting off-target activity of AMN082 resulting in hypo-locomotion. Conclusions These results strongly suggest that activation of the mGlu7 receptor elicits antidepressant-like effects.     

The group III mGlu receptor agonist ACPT-I exerts anxiolytic-like but not antidepressant-like effects, mediated by the serotonergic and GABA-ergic systems

Our earlier studies have demonstrated that (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid ACPT-I, a group III mGlu receptor agonist, produced anxiolytic-like and antidepressant-like actions after central administration. Here we describe the anxiolytic-like effects of ACPT-I after intraperitoneal administration in the stress-induced hyperthermia (SIH), elevated plus-maze (PMT) tests in mice and in the Vogel test in rats. However, the compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of ACPT-I (20 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT_1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635) (0.1 mg/kg s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT2A/C receptor antagonist, did not change the anxiolytic-like effects of ACPT-I. The results of these studies indicate that the GABA-ergic and serotonergic systems are involved in the potential anxiolytic action of ACPT-I.