European Journal of Pharmacology (v.639, #1-3)

Metabotropic glutamate mGlu1 receptors play a modulatory role in the nervous system. They enhance cell excitability, modulate synaptic neurotransmission and are involved in synaptic plasticity. During the last 10 years, several selective metabotropic glutamate mGlu1 receptor competitive antagonists and potentiators have been discovered. These pharmacological tools, together with early and later work in metabotropic glutamate mGlu1 receptor mutant mice have allowed studying the role of the receptor in various aspects of psychiatric illnesses such as anxiety, depression and schizophrenia. We here review the data on selective metabotropic glutamate mGlu1 receptor antagonists in support of their potential as anxiolytic and antidepressant treatments. We propose a rationale for the development of metabotropic glutamate mGlu1 receptor positive allosteric modulators for the treatment of schizophrenia. Potential side effects of blockade and activation of metabotropic glutamate mGlu1 receptors are addressed, with special focus on the differential effects of metabotropic glutamate mGlu1 receptor antagonists in cognition models with positive reinforcement versus those that use aversive learning procedures. Further development of negative allosteric modulators and more drug-like positive allosteric modulators will be required in order to decipher the therapeutic efficacy and safety margin of these compounds in the clinic.
Keywords: Metabotropic glutamate mGlu1 receptor; Negative allosteric modulator; Positive allosteric modulator; Anxiety; Depression; Schizophrenia;

Metabotropic glutamate receptor subtype 5 antagonism in learning and memory by Agnes Simonyi; Todd R. Schachtman; Gert R.J. Christoffersen (17-25).
The role of the metabotropic glutamate receptor 5 (mGlu5 receptor) in learning and memory and other behaviors are reviewed by examining the influence of selective antagonists and genetic knockout on performance. This receptor is involved in spatial learning, contextual fear conditioning, inhibitory avoidance, fear potentiated startle, and conditioned taste aversion. However, mGlu5 receptor antagonists have proven to be ineffective in other learning tasks, such as the delayed-match-to-position test and a three-hole spatial learning task. Locomotion is often decreased by mGlu5 receptor antagonists; and other behaviors such as social interaction and consummatory responses can also be affected. In mGlu5 receptor knockout mice, performance in contextual fear conditioning and spatial water maze tasks is impaired. Although the available evidence is suggestive of an important contribution of mGlu5 receptors to cognitive functions, further studies are needed, particularly those with in vivo evaluation of the role of mGlu5 receptors in selective brain regions in different stages of memory formation.
Keywords: Metabotropic glutamate receptor 5; Spatial learning; Fear conditioning; Avoidance learning; MPEP; MTEP; Locomotion; (Rat); (Mouse);

Metabotropic glutamate (mGlu) receptors provide a mechanism by which the function of NMDA glutamate receptors can be modulated. As NMDA receptor hypofunction is implicated in the etiology of psychiatric disorders, including schizophrenia, the pharmacological regulation of mGlu receptor activity represents a promising therapeutic approach. We examined the effects of the positive allosteric mGlu5 receptor modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), alone and in combination with the NMDA receptor antagonist MK-801, on a task measuring cognitive set-shifting ability. This task measures NMDA receptor-dependent cognitive abilities analogous to those impaired in schizophrenia. Systemic administration of CDPPB (10 and 30 mg/kg i.p) blocked MK-801 (0.1 mg/kg, i.p.)-induced impairments in set-shifting ability. The effect on learning was dose-dependent, with the 30 mg/kg dose having a greater effect than the 10 mg/kg dose across all trials. This ameliorative effect of CDPPB reflected a reduction in MK-801-induced perseverative responding. These results add to the evidence that mGlu5 receptors interact functionally with NMDA receptors to regulate behavior, and suggest that positive modulators of mGlu5 receptors may have therapeutic potential in the treatment of disorders, like schizophrenia, characterized by impairments in cognitive flexibility and memory.
Keywords: Set-shift; Response inhibition; Extradimensional shift; Perseveration; Prefrontal cortex; Schizophrenia; Addiction;

Group 5 metabotropic glutamate (mGlu5) receptors are abundant in forebrain and limbic regions and provide a novel pharmacological target for modulation of cognition. Here, we review recent advances in understanding the electrophysiology of these receptors which reveal a role for mGlu5 receptors in the regulation of tonic and bursting modes of neuronal firing, maintenance of distinct forms of synaptic plasticity, and reversal of detrimental effects of NMDA receptor antagonism on cortical neuronal activity. Furthermore, recordings using recently developed positive allosteric modulators of the mGlu5 receptor suggest that these agents have an electrophysiological profile comparable to the antipsychotic agent clozapine. These findings, in conjunction with behavioral evidence from preclinical studies of cognition, suggest a potential precognitive profile for the mGlu5 receptor potentiators.
Keywords: Metabotropic glutamate receptor 5; NMDA glutamate receptor; Schizophrenia; Prefrontal cortex; Cognitive enhancer;

Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator by Holger Rosenbrock; Gert Kramer; Scott Hobson; Eliza Koros; Marc Grundl; Matthias Grauert; Klaus G. Reymann; Ulrich H. Schröder (40-46).
The NMDA (N-methyl-D-aspartate)-receptor is fundamentally involved in cognitive functions. Recent studies demonstrated a functional interaction between the metabotropic glutamate receptor 5 (mGlu5 receptor) and the NMDA-receptor in neurons. In rat hippocampal slices, it was shown that activation of mGlu5 receptor by a positive modulator in the presence of a subthreshold agonist concentration potentiated NMDA-receptor mediated currents and phosphorylation of intracellular signalling proteins. In the present study, we investigated the functional interaction of mGlu5 receptor and NMDA-receptor by the selective mGlu5 receptor positive modulator ADX-47273 in-vitro and in-vivo. In rat primary neurons, this compound potentiated Ca2+ mobilization in the presence of a subthreshold concentration of the mGluR1/5 agonist DHPG (0.3 µM) with an EC50 of 0.28 ± 0.05 µM. NMDA-induced Ca2+-mobilization in primary neurons could be potentiated when neurons were pre-stimulated with 1 µM ADX-47273 in the presence of 0.3 µM DHPG. The specific mGlu5 receptor antagonist MPEP and the Src-family kinase inhibitor PP2 blocked this potentiation demonstrating the functional interaction of the NMDA-receptor and mGlu5 receptor in neurons. Furthermore, ADX-47273 elicited an enhancement of NMDA-receptor dependent long-term potentiation in rat hippocampal slices that could be reversed by MPEP. After intraperitoneal administration to rats, ADX-47273 showed a dose-dependent reduction of NMDA-receptor antagonist (ketamine) induced hyperlocomotion, supporting the mechanistic interaction of the NMDA-receptor and mGlu5 receptor in-vivo. In conclusion, these findings further support the idea of a functional interaction between the mGlu5 receptor and NMDA-receptor, which may provide a pharmacological strategy for addressing CNS diseases with cognitive impairments linked to NMDA-receptor hypofunction.
Keywords: NMDA(N-methyl-D-aspartate)-receptor; mGlu5 receptor; Metabotropic glutamate receptor 5; Positive allosteric modulator; ADX-47273; Long-term potentiation;

Glutamate plays a pivotal role in regulating drug self-administration and drug-seeking behavior, and the past decade has witnessed a substantial surge of interest in the role of Group I metabotropic glutamate receptors (mGlu1 and mGlu5 receptors) in mediating these behaviors. As will be reviewed here, Group I mGlu receptors are involved in normal and drug-induced synaptic plasticity, drug reward, reinforcement and relapse-like behaviors, and addiction-related cognitive processes such as maladaptive learning and memory, behavioral inflexibility, and extinction learning. Animal models of addiction have revealed that antagonists of Group I mGlu receptors, particularly the mGlu5 receptor, reduce self-administration of virtually all drugs of abuse. Since inhibitors of mGlu5 receptor function have now entered clinical trials for other medical conditions and appear to be well-tolerated, a key question that remains unanswered is — what changes in cognition are produced by these compounds that result in reduced drug intake and drug-seeking behavior? Finally, in contrast to mGlu5 receptor antagonists, recent studies have indicated that positive allosteric modulation of mGlu5 receptors actually enhances synaptic plasticity and improves various aspects of cognition, including spatial learning, behavioral flexibility, and extinction of drug-seeking behavior. Thus, while inhibition of Group I mGlu receptor function may reduce drug reward, reinforcement, and relapse-related behaviors, positive allosteric modulation of the mGlu5 receptor subtype may actually enhance cognition and potentially reverse some of the cognitive deficits associated with chronic drug use.
Keywords: Drug addiction; Rodent model; Glutamate; Metabotropic glutamate receptor; Allosteric modulator; Learning; Memory; Cognition; Extinction;

Metabotropic glutamate receptors (mGlu receptors), with their unique signaling systems and pharmacological characteristics, have emerged as a new topic in excitatory amino acid research. Among them, the unique distribution of group II mGlu receptors, such as mGlu2 and mGlu3 receptors, and the involvement of these receptors in the regulation of neurotransmission are particularly interesting. Recently, potent agonists for mGlu2/3 receptor have been synthesized, and their pharmacological roles have been intensively investigated using animal models. mGlu2/3 receptors clearly have crucial roles in the central nervous system, and accumulating evidence in both rodents and human studies has suggested that agonists for mGlu2/3 receptors may be beneficial for the treatment of psychiatric disorders such as schizophrenia. Possible neuronal circuits through which mGlu2/3 receptor agonists exert their pharmacological effects have also been investigated.
Keywords: mGlu2/3 receptor; mGlu2 receptor; mGlu3 receptor; Schizophrenia; Antipsychotic;

Dysregulation of glutamate neurotransmission may play a role in cognitive deficits in schizophrenia. Manipulation of glutamate signaling using drugs acting at metabotropic glutamate receptors has been suggested as a novel approach to treating schizophrenia-related cognitive dysfunction. We examined how the metabotropic glutamate receptor 2/3 agonist LY379268 and the metabotropic glutamate receptor 2/3 antagonist LY341495 altered phencyclidine-induced disruptions in performance in the 5-choice serial reaction time task. This test assesses multiple cognitive modalities characteristically impaired in schizophrenia that are disrupted by phencyclidine administration. Acute LY379268 alone did not affect 5-choice serial reaction time task performance, except for nonspecific response suppression at high doses. Acute LY379268 administration exacerbated phencyclidine-induced disruption of attentional performance in this task, while acute LY341495 did not alter 5-choice serial reaction time task performance during phencyclidine exposure. Chronic LY341495 impaired attentional performance in the 5-choice serial reaction time task by itself, but attenuated phencyclidine-induced excessive timeout responding. The mixed effects of metabotropic glutamate receptor 2/3 agonism and antagonism on cognitive performance under baseline conditions and after disruption with phencyclidine demonstrate that different aspects of cognition may respond differently to a given pharmacological manipulation, indicating that potential antipsychotic or pro-cognitive medications need to be tested for their effects on a range of cognitive modalities. Our findings also suggest that additional mechanisms, besides cortical glutamatergic transmission, may be involved in certain cognitive dysfunctions in schizophrenia.
Keywords: Schizophrenia; Phencyclidine; Metabotropic glutamate receptor; LY379268; LY341495; Cognition;

Recently, a metabotropic glutamate2/3 (mGlu2/3) receptor agonist prodrug was found to improve both the positive and negative symptoms of schizophrenic patients. Thus far, however, definitive data directly describing the effects of mGlu2/3 receptor agonists on cognition in schizophrenic patients is lacking. In this review, we will first describe the location of mGlu2 and mGlu3 receptors with respect to cellular compartments in cortical circuits of both the prefrontal cortex and the hippocampal formation. We will then address the function of mGlu2 and mGlu3 receptors in both macrocircuits and microcircuits involving the prefrontal cortex and hippocampal formation. Imbalance within and between macrocircuits, including the re-entrant cortico-striatal-thalamic loops; the trisynaptic organization of the hippocampal formation; and the ascending reticular activating system/monoaminergic brainstem nuclei projecting throughout the neural axis, appear central to understanding both the pathophysiology and therapeutic approaches for treating the pervasive cognitive dysfunction associated with schizophrenia. Understanding the function of mGlu2 and mGlu3 receptors in these macrocircuits also may provide answers to currently conflicting data between some preclinical studies and the clinical studies seemingly predicting impairment and improvement in cognitive function with activation of mGlu2 and mGlu3 receptors.
Keywords: Thalamocortical; Corticostriatal; Hippocampus; Prefrontal cortex; Impulsivity; Psychosis;

The difference in effect of mGlu2/3 and mGlu5 receptor agonists on cognitive impairment induced by MK-801 by Karel Vales; Jan Svoboda; Kristina Benkovicova; Vera Bubenikova-Valesova; Ales Stuchlik (91-98).
The manipulation of glutamate neurotransmission could represent a potential strategy for the pharmacotherapy of schizophrenic symptoms. Preclinical studies suggest that two subtypes of metabotropic glutamate (mGlu) receptors such as mGlu2/3 and mGlu5 receptors have the potential to ameliorate deficits in schizophrenia. In our study we evaluated the role of a non-specific mGlu receptor agonist ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid; 1S,3R-ACPD), mGlu5 receptor agonist or positive modulators ((RS)-2-Chloro-5-hydroxyphenylglycine;CHPG; [(3-Fluoro-phenyl)methylene]hydrazone-3-fluorobenzaldehyde; DFB; 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; CDPPB) and a mGlu2/3 receptor agonist (2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyrdinylmethyl)ethanesulfonamide hydrochloride; LY-487379) on performance in a cognitive task (Active Allothetic Place Avoidance) after sub-chronic administration of 5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imine; MK-801 . The Active Allothetic Place Avoidance task is suitable for assessing the executive function and attention of animals and was previously validated for testing the effect of anti-psychotics. Application of the mGlu2/3 receptor agonist had no effect on cognitive impairment induced by MK-801. However, the mGlu5 receptor agonists ameliorated cognitive impairment induced by MK-801 without affecting locomotion. In conclusion, the mGlu5 receptor agonists could be effective in the treatment of cognitive deficits in patients with schizophrenia. However, the pro-cognitive effect of the agonist of mGlu2/3 receptors was not demonstrated in the present study.
Keywords: MK-801; Animal model of schizophrenia; mGlu receptor; Cognition; Behavior; AAPA (Active Allothetic Place Avoidance);

Pharmacological effects of metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice by Hirohiko Hikichi; Miho Nishino; Miyuki Fukushima; Akio Satow; Shunsuke Maehara; Hiroshi Kawamoto; Hisashi Ohta (99-105).
Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animals using acoustic prepulse inhibition of the startle. Both classical and atypical antipsychotics have been shown to improve prepulse inhibition in DBA/2J mice, a non-pharmacological model for impaired sensorimotor gating. The purpose of the present study was to clarify whether metabotropic glutamate receptors participate in control of sensorimotor gating. We evaluated various metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice. This basal level of prepulse inhibition in DBA/2J mice was increased by only the mGlu1 receptor antagonists [2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one] (CFMTI), 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-α]benzimidazole-2-carboxamide hydrochloride (YM-298198), and (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685). There was no effect after treatments with the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the mGlu2/3 receptor agonist (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), the mGlu2/3 receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), the mGlu7 receptor agonist N,N -dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the mGlu7 receptor antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one (MMPIP), or the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG). These findings indicate that inhibition of mGlu1 receptor selectively increases prepulse inhibition in DBA/2J mice and suggest that mGlu1 receptor antagonists could be a novel treatment for some aspects of schizophrenia.
Keywords: mGlu receptor; Prepulse inhibition; DBA/2J (mouse);

Effects of a novel metabotropic glutamate receptor 7 negative allosteric modulator, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one (MMPIP), on the central nervous system in rodents by Hirohiko Hikichi; Takeshi Murai; Shoki Okuda; Shunsuke Maehara; Akio Satow; Satoko Ise; Miho Nishino; Gentaroh Suzuki; Hiroshi Takehana; Mikiko Hata; Hisashi Ohta (106-114).
We recently identified 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), the first allosteric metabotropic glutamate (mGlu) 7 receptor-selective negative allosteric modulator. In this study, we examined the in vivo pharmacological effects of MMPIP on the central nervous system. MMPIP was distributed into the brain after systemic administration in both mice and rats. Pharmacokinetic study revealed that the half-life of MMPIP in circulation was about 1 h in rats. Results of various behavioral studies revealed that MMPIP impaired non-spatial and spatial cognitive performances in the object recognition test and the object location test in mice, respectively. In rats, MMPIP increased time to complete the task in the 8-arm radial maze test without increasing error. In addition to impairing cognition, MMPIP decreased social interaction with reduction of line crossing in rats, while MMPIP had no effects on locomotor activity in rats and mice, rota-rod performance in mice, prepulse inhibition in rats, maternal separation-induced ultrasonic vocalization in rat pups, stress-induced hyperthermia in mice, or the tail suspension test in mice. No analgesic effects of MMPIP were detected in either the tail immersion test or formalin test in mice. MMPIP did not alter the threshold for induction of seizures by electrical shock or pentylenetetrazole in mice. These findings suggest that blockade of mGlu7 receptors by MMPIP may modulate both non-spatial and spatial cognitive functions without non-selective inhibitory effects on the central nervous system.
Keywords: MMPIP (6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one); MGlu7 (metabotropic glutamate 7) receptor; Cognition; Central nervous system; (Mouse); (Rat);

Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction by Khaled Moussawi; Peter W. Kalivas (115-122).
Drug addiction is characterized by maladaptive decision-making and dysfunctional brain circuitry regulating motivated behaviors, resulting in loss of the behavioral flexibility needed to abstain from drug seeking. Hence, addicts face high risk of relapse even after prolonged periods of abstinence from drug use. This is thought to result from long-lasting drug-induced neuroadaptations of glutamate and dopaminergic transmission in the mesocorticolimbic and cortico-striatal circuits where group II metabotropic glutamate receptors (mGlu2/3 receptors) are densely expressed. mGlu2/3 receptors presynaptically control glutamate as well as dopamine release throughout the mesocorticolimbic structures involved in reward processing and drug seeking, and their function is reduced after prolonged exposure to drugs of abuse. In pre-clinical models, mGlu2/3 receptors have been shown to regulate both reward processing and drug seeking, in part through the capacity to control release of dopamine and glutamate respectively. Specifically, mGlu2/3 receptor agonists administered systemically or locally into certain brain structures reduce the rewarding value of commonly abused drugs and inhibit the reinstatement of drug seeking. Given the ability of mGlu2/3 receptor agonists to compensate for and possibly reverse drug-induced neuroadaptations in mesocorticolimbic circuitry, this class of receptors emerges as a new therapeutic target for reducing relapse in drug addiction.
Keywords: Addiction; Glutamate; Group II metabotropic glutamate receptor (mGlu2/3 receptor); LY379268; LY341495;

Metabotropic glutamate receptor 7: At the interface of cognition and emotion by Richard M. O'Connor; Beate C. Finger; Peter J. Flor; John F. Cryan (123-131).
Understanding the complex interaction between stress and genetics that leads to the manifestation of disorders such as depression, anxiety, and cognitive dysfunction is one of the key areas of research in modern neuroscience. Growing evidence suggests that the glutamatergic system may be a relevant therapeutic target for such disorders. Glutamate is the neurotransmitter at the vast majority of excitatory synapses in the brain, and metabotropic glutamate (mGlu) receptor subtypes (mGlu1 receptor–mGlu8 receptor) act as important pre- and postsynaptic regulators of neurotransmission in the central nervous system (CNS), providing a mechanism by which fast synaptic responses through ligand-gated cation channels can be fine-tuned. Thus mGlu receptors are poised to participate in a wide variety of functions of the CNS. The presynaptic mGlu7 receptor shows the highest evolutionary conservation within the family and it is thought to regulate neurotransmitter release. The mGlu7 receptor is also the most widely distributed of the presynaptic mGlu receptors and is present at a broad range of synapses that are postulated to be critical for both normal CNS function and a range of psychiatric and neurological disorders. A growing body of evidence suggests that the mGlu7 receptor is a key player in shaping synaptic responses at glutamatergic synapses as well as being a key regulator of inhibitory GABAergic transmission. The development of selective pharmacological and genetic tools has allowed for the unravelling of mGlu7 receptor function in a host of physiological and behavioural processes. Knockout mice and siRNA knockdown has pointed to a role of the mGlu7 receptor in anxiety, extinction of fear and aversion learning, spatial memory and the hormonal response to stress. In addition, these studies are largely supported by pharmacological manipulation of mGlu7 receptor using the selective modulator N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), although paradoxical effects with this agonist have also emerged. Together these data suggest that the mGlu7 receptor is an important regulator of glutamatergic function, of fear and aversion and cognition and thus this receptor represents an innovative therapeutic target for stress-related disorders at the interface of cognition and anxiety.
Keywords: Keywords:; Glutamate; mGlu7 receptor; Psychiatric; Cognition; Emotion;