Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia

European Journal of Pharmacology 639 (2010) 59–66

Contents lists available at ScienceDirect

European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Review

Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia Shigeyuki Chaki ⁎ Discovery Pharmacology, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan

a r t i c l e

i n f o

Article history: Received 1 August 2009 Received in revised form 19 November 2009 Accepted 7 December 2009 Available online 2 April 2010 Keywords: mGlu2/3 receptor mGlu2 receptor mGlu3 receptor Schizophrenia Antipsychotic

a b s t r a c t 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. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular properties and distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glutamate hypothesis for schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of mGlu2/3 receptor in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Potency of mGlu2/3 agonists in animal models of schizophrenia . . . . . . . . . . . . . 4.2.1. Antipsychotic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Effect on cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3. Possible involvement of mGlu3 receptor in the action of mGlu2/3 receptor agonists 4.3. Neuronal mechanisms underlying the antipsychotic actions of mGlu2/3 receptor agonists . 4.3.1. Regulation of glutamate release . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Regulation of dopamine release . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Interaction with 5-HT2A receptor . . . . . . . . . . . . . . . . . . . . . . . 5. Clinical results for mGlu2/3 receptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Glutamate is the major excitatory neurotransmitter in the brain, and is involved in a wide range of physiological events in the central nervous system including emotion, cognition, and motor functions.

⁎ Tel.: +81 48 669 3065; fax: +81 48 652 7254. E-mail address: [email protected]. 0014-2999/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.12.041

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

59 60 60 60 60 60 60 61 61 61 61 63 63 64 64 65

At present, glutamate receptors are classified into two major types: ionotropic glutamate receptors (iGlu receptors), which have an ion channel structure, and metabotropic glutamate receptors (mGlu receptors), which are coupled to G-proteins (Nakanishi, 1992; Nakanishi and Masu, 1994). iGlu receptors are also classified into Nmethyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and kainate receptors (Nakanishi, 1992; Nakanishi and Masu, 1994). In addition to iGlu receptors which facilitate fast synaptic transmission, mGlu receptors also have

60

S. Chaki / European Journal of Pharmacology 639 (2010) 59–66

isoforms (mGlu1–mGlu8). mGlu receptors are currently classified into three groups based on their sequence homology, second messenger coupling and pharmacological characteristics (Pin and Duvoisin, 1992; Schoepp and Conn, 1993; Conn and Pin, 1997). Group I mGlu receptors include mGlu1 and mGlu5 receptors, which are coupled to phospholipase C, while both group II mGlu receptors (mGlu2, mGlu3) and group III mGlu receptors (mGlu4, mGlu6, mGlu7, mGlu8) are negatively coupled to adenylyl cyclase activity. Among these mGlu receptors, the physiological roles mediated by mGlu2/3 receptors have been thoroughly investigated using potent and selective mGlu2/3 receptor agonists. A growing body of evidence shows that mGlu2/3 receptor agonists exhibit significant pharmacological effects in numerous models of experimental animals, including models for psychiatric disorders, stroke and epilepsy. Given accumulating evidence in animal models and positive results in a recently reported clinical trial, this review will focus on the possible therapeutic application of mGlu2/3 receptor agonists for the treatment of schizophrenia. 2. Molecular properties and distribution Although mGlu receptors are members of the G-protein coupled receptor (GPCR) family, mGlu receptors have no sequence homology to the known GPCRs for neurotransmitters. Instead, mGlu receptors have similarity to the calcium sensor receptor of the parathyroid (Brown et al., 1993) and to the GABAB receptor (Kaupmann et al., 1997). mGlu receptors, compared with other conventional GPCRs, have a larger N-terminus extracellular domain that has been shown to confer glutamate binding, agonist activation of the receptor, and subtype selectivity (Takahashi et al., 1993). In contrast to group I mGlu receptors which are coupled to the stimulation of phosphatidylinositol hydrolysis/Ca2+ signal transduction, both mGlu2 and mGlu3 receptors are negatively coupled to cAMP formation. Thus, agonists for mGlu2/3 receptors and glutamate potently inhibited forskolin-stimulated cAMP formation in CHO cells expressing mGlu2 or mGlu3 receptor (Tanabe et al., 1992, 1993). The effect of these agonists was strongly inhibited by pertussis toxin. The distributions of mGlu2 and mGlu3 receptors have been investigated in the brain using in situ hybridization. Although the hybridization signals were widely distributed in the brain, the most prominent expression of mGlu2 mRNA was seen in the Golgi cells of the cerebellum. The marked expression of mGlu2 mRNA was further observed in the neurons of the accessory and external part of the anterior olfactory bulb, pyramidal neurons in the entorhinal and parasubicular cortical regions, and granule cells of the dentate gyrus (Ohishi et al., 1993a). By contrast, mGlu3 mRNA was highly expressed in neuronal cells of the cerebral cortex and the caudate-putamen and in granule cells of the dentate gyrus (Tanabe et al., 1993). Unlike the other mGlu mRNAs, mGlu3 mRNA was highly expressed in glial cells throughout the regions of the brain (Tanabe et al., 1993). In an immunohistochemical study, intense mGlu2-like immunoreactivity was seen mainly in neuropils of the cerebral cortical regions, hippocampus, olfactory bulb, some diencephalic nuclei, dorsal cochlear nucleus and cerebellar cortex, which is in good accord with the distribution of mRNA (Neki et al., 1996). 3. Glutamate hypothesis for schizophrenia In addition to the well-established “dopamine hypothesis of schizophrenia”, abnormalities in glutamate transmissions have been suggested to be involved in the pathophysiology of schizophrenia. The glutamate hypothesis stemmed from the following findings: 1) significantly lower levels of glutamate are found in the cerebrospinal fluid (CSF) and postmortem brain tissue of schizophrenic patients (Kim et al., 1980; Tsai et al., 1995); 2) CSF glutamate levels are inversely correlated with the severity of positive symptoms in

unmedicated patients (Faustman et al., 1999); 3) phencyclidine (PCP) and ketamine, two non-competitive NMDA receptor antagonists, produced transient psychosis and disrupted affect and cognitive impairment in healthy volunteers, similar to the symptoms of schizophrenia (Javitt and Zukin, 1991; Krystal et al., 1994; Lahti et al., 2001; Newcomer et al., 1999), and led to the profound exacerbation of preexisting symptoms in schizophrenic patients (Lahti et al., 2001); and 4) NMDA receptor antagonists and the transgenic manipulation of an NMDA receptor subunit (NR1) induced behavioral abnormalities (increased locomotor activity, reduced social interaction, and cognitive dysfunction) that were ameliorated by antipsychotic treatments (Geyer et al., 2001; Gleason and Shannon, 1997; Mohn et al., 1999). Thus, glutamatergic dysfunction, particularly the hypofunction of NMDA receptors may have an important role in the pathophysiology of schizophrenia. Abnormalities in glutamate transmission have also been suggested to be deeply involved in the cognitive aspects of schizophrenia, which are considered to be the core features of this illness. Thus, the application of an NMDA antagonist into the dorsolateral prefrontal cortex (but not to the primary visual cortex) impaired working memory performance in monkeys (Dudkin et al., 2001). Consistent with the above-mentioned hypothesis, D-serine and sarcosine, both of which increase NMDA receptor activities, have reportedly improved cognitive impairment in rodent models and in schizophrenic patients (Karasawa et al., 2008; Coyle and Tsai, 2004). 4. Role of mGlu2/3 receptor in schizophrenia 4.1. Human studies Alterations of mGlu2 or mGlu3 receptor levels in the brain region of postmortem of schizophrenic subjects have been reported. Most studies have indicated alterations of mGlu3 receptor expression, although one study reported that mRNA levels of mGlu2 but not mGlu3 were reduced in the cortex of schizophrenic subjects untreated with antipsychotics (González-Maeso et al., 2008). Corti et al. (2007) reported a significant decrease in dimeric/oligomeric forms of mGlu3 receptor in the prefrontal cortex (Brodmann area 10) of schizophrenic subjects, while monomeric forms of mGlu3 receptor were not changed. Moreover, mGlu3 receptor protein levels have recently been reported to be decreased in the prefrontal cortex of schizophrenic subjects, while mGlu2 receptor levels were unaltered (Ghose et al., 2009). In addition to changes in expression levels, an association between polymorphisms in mGlu3 gene locus (GRM3) and schizophrenia has been reported (Chen et al., 2005; Egan et al., 2004; Fujii et al., 2003). In addition, an intronic variation in GRM3 has been reported to be associated with behavioral (poorer performance on several cognitive tests of prefrontal and hippocampal function), physiological (deleterious activation patterns in the cortical regions) and molecular (lower level of N-acetylaspartate and EAAT2 in the prefrontal cortex) phenotypes related to schizophrenia, suggesting that GRM3 genotype alters specific molecular pathways related to pathophysiology of schizophrenia, and thereby increases risk of schizophrenia (Egan et al., 2004). Moreover, an exon 3 single-nucleotide polymorphism associated with schizophrenia has been reported to predict increased expression of the GRM3Δ4 splice variant, which has an exon 4 deletion and encodes a truncated form of the receptor (Sartorius et al., 2008). 4.2. Potency of mGlu2/3 agonists in animal models of schizophrenia 4.2.1. Antipsychotic activity LY354740, an mGlu2/3 receptor agonist, reportedly attenuated PCP-induced locomotor hyperactivity and the stereotypy score when administered at a dose that did not affect spontaneous locomotor

S. Chaki / European Journal of Pharmacology 639 (2010) 59–66

activity (Moghaddam and Adams, 1998). Similar to the effect of an NMDA receptor antagonist, the attenuation of locomotor hyperactivity was also observed when other mGlu2/3 receptor agonists, such as LY404039 (Rorick-Kehn et al., 2007), LY379268 (Cartmell et al., 2000), and MGS0008 and MGS0028 (Nakazato et al., 2000), were administered. Both LY379268 and LY404039 have also been reported to inhibit locomotor hyperactivity induced by amphetamine (Galici et al., 2005; Rorick-Kehn et al., 2007). Moreover, MGS0008, MGS0028 and LY404039 have been reported to inhibit conditioned avoidance responses (Takamori et al., 2003; Rorick-Kehn et al., 2007). All of the above-mentioned findings suggest that mGlu2/3 receptor agonists could be potentially useful for the treatment of positive symptoms of schizophrenia. The effects of LY404039 on PCP or amphetamineinduced behaviors (increased ambulation) were absent in knockout mice lacking mGlu2 or mGlu2/3 receptors but not in mice lacking the mGlu3 receptor, indicating that the activation of mGlu2 but not mGlu3, is responsible for the antipsychotic actions of mGlu2/3 receptor agonists (Fell et al., 2008). This finding was further supported by the result that a selective mGlu2 receptor potentiator, LY487379, had the same effect as the mGlu2/3 receptor agonists on PCP or amphetamine-induced hyperlocomotion (Galici et al., 2005). In contrast, atypical antipsychotics such as clozapine and risperidone inhibited PCP-induced behavior in both wild type and mGlu2/3 receptor null mice (Fell et al., 2008). Thus, mGlu2/3 receptor agonists may exert antipsychotic effects through different neuronal mechanisms from currently prescribed antipsychotics. 4.2.2. Effect on cognition Most schizophrenic patients suffer from cognitive impairment, which is not alleviated by treatments that successfully attenuate positive symptoms. Thus, cognitive impairment represents the highest medical need in the development of new antipsychotics. An improvement in cognitive dysfunction after treatment with mGlu2/3 receptor agonists has been reported. LY354740 was the first agonist reported to improve PCP-impaired performance in a T-maze discretetrial delayed alteration task (Moghaddam and Adams, 1998). LY354740 also has been reported to reverse deficits in social discrimination (possibly reflecting a disturbance in selective attention) induced by neonatal treatment with PCP, as did clozapine and a glycine transporter inhibitor (Harich et al., 2007). These results suggest that stimulation of the mGlu2/3 receptor may be effective for alleviating cognitive dysfunctions associated with schizophrenia. Interestingly, an improvement in deficits of social discrimination was also observed after treatment with LY487379, a selective mGlu2 receptor potentiator (Harich et al., 2007). Thus, the stimulation of the mGlu2 receptor, but not the mGlu3 receptor, may be responsible for this effect, as in the case of the attenuation of psychostimulantinduced locomotor hyperactivity. In contrast, LY354740 reportedly induced working memory deficits in a delayed matching and nonmatching to position task and spatial memory deficits in a Morris water maze (Higgins et al., 2004), while LY341495 or MGS0039, an mGlu2/3 receptor antagonist, enhances spatial learning in Morris water maze task (Higgins et al., 2004), and short-term social memory in social recognition test (Shimazaki et al., 2007). Thus, blockade of mGlu2/3 receptor may have pro-cognitive effects. This discrepancy may be attributable to the assumption that mGlu2/3 agonists function differently under normal conditions, compared with their performances in imbalanced systems induced by PCP. Moreover, LY354740 was recently reported not to improve either PCP-induced working memory deficits in a spontaneous alternation task or PCP-induced amnesia in a passive avoidance task, while impairing working memory on its own (Schlumberger et al., 2009). Therefore, the effect of mGlu2/3 receptor agonists on cognitive dysfunctions may be taskdependent or may depend on the conditions of their use (differences in dosage of LY354740 and route of administration). It should be noted that Harich et al. (2007) used neurodevelopmental models,

61

while Schlumberger et al. (2009) induced working memory deficits by acute treatment with PCP. Thus, neurodevelopmental model may more represent schizophrenic-like state. Nevertheless, a thorough investigation in other models is needed to obtain a clearer idea of the potential effects of mGlu2/3 receptor agonists on cognitive dysfunction. Sensorimotor gating, measured by prepulse inhibition (PPI), is a fundamental form of information processing that is deficient in schizophrenic patients. mGlu2/3 receptor agonists such as LY379268 and LY314582 did not significantly reverse amphetamine- or the PCPinduced disruption of PPI (Galici et al., 2005; Henry et al., 2002). Likewise, the subchronic administration of LY354740 for 8 days did not reverse ketamine-induced deficits in PPI (Imre et al., 2006). In contrast, LY487379, a selective mGlu2 receptor potentiator, significantly improved amphetamine-disrupted PPI but not PCP-disrupted PPI (Galici et al., 2005). The selective stimulation of the mGlu2 receptor might have beneficial effects on deficiencies in sensorimotor gating that are not observed with mGlu2/3 receptor agonists. Although highly speculative, mGlu3 receptor activation might conceivably exert an action that counteracts the effect of mGlu2 receptor activation in this model. 4.2.3. Possible involvement of mGlu3 receptor in the action of mGlu2/3 receptor agonists Although involvement of mGlu3 receptor in the pharmacological actions of mGlu2/3 receptor agonists has not been directly demonstrated in animal studies, possible involvement of mGlu3 receptor in antipsychotic actions has been suggested. N-acetyl-aspartyl-glutamate (NAAG), a widely distributed endogenous neuropeptide in the mammalian brain, has been reported to be a selective endogenous agonist for mGlu3 receptor (Neale et al., 2000). NAAG is inactivated by glutamate carboxypeptidase II (GCP II) and glutamate carboxypeptidase III (GCP III) in that GCP II is responsible for most of NAAG degradation in the central nervous system (Neale et al., 2005). ZJ43, an inhibitor of GCP II, has been reported to attenuate PCP-induced locomotor hyperactivity and PCP-reduced negative symptom in a resident-intruder assay, both of which were reversed with LY341495 (Olszewski et al., 2008). Therefore, increase in NAAG by blocking GCP II exhibits antipsychotic effects in animal models, and these effects may be ascribed to stimulation of mGlu3 receptor. Of note, increased levels of GCP II have been reported in the prefrontal cortex of schizophrenic subjects (Ghose et al., 2009), which is consistent with the hypothesis that decrease in the endogenous mGlu3 receptor agonist may cause schizophrenic-like symptoms. In addition to presynaptic action, mGlu3 receptor expressed in glial cells has been suggested to be involved in antipsychotic actions. Stimulation of mGlu3 receptor increases expression of glial glutamate transporters (GLT-1, GLAST) (Aronica et al., 2003), which may contribute to elimination of excess glutamate, and generates the formation of transforming growth factor β1 (Bruno et al., 1998), contributing to enhancement of dendritic growth and spine formation, both of which are reduced in schizophrenia. In contrast, it should be noted that Fricker et al. (2009) reported that purified NAAG did not show agonist activity at mGlu3 receptor, and they assumed that the previous findings with NAAG may be ascribed to contaminating glutamate present in commercially available sources of NAAG. Therefore, role of mGlu3 receptor in the actions of antipsychotic effect needs to be solved. 4.3. Neuronal mechanisms underlying the antipsychotic actions of mGlu2/3 receptor agonists 4.3.1. Regulation of glutamate release The systemic administration of NMDA receptor antagonists such as PCP and ketamine, reportedly increase glutamate release in the prefrontal cortex, while mGlu2/3 receptor agonists such as LY354740

62

S. Chaki / European Journal of Pharmacology 639 (2010) 59–66

and LY379268, attenuate this process (Lorrain et al., 2003; Moghaddam and Adams, 1998). The increase in glutamate release in the prefrontal cortex (i.e., hyperfrontality) caused by NMDA receptor dysfunction may be related to the pathophysiology of schizophrenia. The injection of an NMDA receptor antagonist into the medial prefrontal cortex reportedly increased glutamate release and impaired attentional performance in the 5-choice serial reaction task (Calcagno et al., 2009); thus, the dysfunction of NMDA receptors within the prefrontal cortex may increase glutamate release, thereby impaired working memory. Deficient glutamate transmission through the NMDA receptor in the dorsolateral prefrontal cortex (DLPFC) has been postulated to be involved in the disturbance of central executive function observed in schizophrenic subjects, since the injection of an NMDA receptor antagonist into the DLPFC impairs working memory performance in monkeys (Dudkin et al., 2001). The level of GAD67 (a 67-kilodalton isoform of glutamic acid decarboxylase) mRNA in parvalbumin (PV) positive chandelier GABA neurons innervating pyramidal neurons was reduced in the DLPFC of patients with schizophrenia (Lewis and Gonzalez-Burgos, 2006; Volk et al., 2000). Because this network is involved in the synchronization of pyramidal neurons, which is important for working memory, disturbances in this network may be attributable to working memory dysfunction in schizophrenia. Several lines of evidence suggest that PV-positive GABA neurons strongly express NR1, and are particularly sensitive to reductions in glutamate transmission through the NMDA receptor (Lewis and Moghaddam, 2006). Thus, a reduction in PVpositive GABA interneurons could conceivably be a downstream consequence of impaired NMDA receptor mediated glutamatergic inputs to these neurons, and the resulting disinhibition of pyramidal neurons activate pyramidal neurons, leading to an increase in glutamate release and thereby impairing the synchronized neuronal activity that is required for working memory function (Fig. 1A). Other data suggest that glutamatergic hyperactivity may emerge via other mechanisms. Lorrain et al. (2003) have suggested that a dysfunction in the NMDA receptor in brain areas other than the prefrontal cortex may cause an increase in glutamate release, since the injection of ketamine into the medial prefrontal cortex did not increase glutamate release, while the systemic injection of the same compound increased it. Conn et al. (2009) presumed that the hypofunction of the NMDA receptor on midbrain inhibitory GABA

projection neurons possibly resulted in the disinhibition of glutamatergic thalamocortical inputs to pyramidal neurons in the prefrontal cortex, leading to an enhancement in glutamate release in this region (Fig. 1B). In any case, the inhibition of increased glutamate release in the frontal cortex is involved in the pharmacological actions of mGlu2/3 receptor agonists. The injection of LY379268 into the medial prefrontal cortex reportedly blocks ketamine-increased glutamate release in this region (Lorrain et al., 2003), indicating that mGlu2/3 receptor agonists may act within the prefrontal cortex to reduce increase in glutamate flow. The disinhibition of glutamate release is also presumed to account for increases in human and rodent frontal cortex metabolism following the administration of NMDA receptor antagonists. Regional cerebral blood flow, which reflect hypermetabolism and may be associated with an increase in glutamate release, markedly increased in the frontal and cingulated cortices following ketamine administraton in both healthy volunteers and schizophrenic patients, with schizophrenic patients exhibiting a higher elevation (Holcomb et al., 2005). Likewise, the NMDA receptor antagonist PCP produced a robust increase in the relative cerebral blood volume (rCBV) in discrete cortico-limbo-thalamic regions including the prefrontal cortex in rats, as determined by pharmacological magnetic resonance imaging (Gozzi et al., 2008). Interestingly, the mGlu2/3 receptor agonist LY354740 attenuated the increase in rCBV induced by PCP administration, suggesting that LY354740 suppresses metabolic hyperactivity in discrete brain regions including the frontal cortex, presumably by inhibiting increases in glutamate release. In contrast, PCP-induced glutamate release in the prefrontal cortex was not reversed by antipsychotics such as clozapine, haloperidol or M100907, a selective 5-HT2A receptor antagonist (Adams and Moghaddam, 2001). PCP-induced glutamate release may occur secondary to the activation of the 5-HT2A receptor, because PCP also increases 5-HT release and 5-HT2A-mediated transmission facilitates glutamate release in the prefrontal cortex. However, the above findings suggest that PCP-induced glutamate release is not dependent on 5-HT2A receptor mediated mechanisms, and mGlu2/3 receptor agonists may have different effects on cognitive dysfunction from those of currently prescribed antipsychotics. For reference, the mGlu2/3 receptor also functions as an autoreceptor on thalamocortical afferents upon which 5-HT2A receptor activation induces glutamate

Fig. 1. Proposed schema for the regulation of glutamatergic neuronal activity in the prefrontal cortex. (A) Hypofunction of NMDA receptors expressed on parvalbumine positive GABAergic interneurons leads to the disinhibition of pyramidal neurons in the prefrontal cortex, possibly causing an increase in glutamate release. (B) Hypofunction of NMDA receptors expressed on GABAergic projection neurons in subcortical regions (e.g., nucleus accumbens) leads to the disinhibition of glutamatergic thalamocortical neurons that project to pyramidal neurons in the prefrontal cortex, causing an increase in glutamate release. The stimulation of mGlu2/3 receptors reduces the increase in glutamate release presynaptically.

S. Chaki / European Journal of Pharmacology 639 (2010) 59–66

release; consequently, mGlu2/3 receptor agonists also attenuate 5HT2A-receptor-mediated glutamate release in the medial prefrontal cortex (see 4-3-3). 4.3.2. Regulation of dopamine release Hyperactive accumbal dopaminergic activity has been presumed to be deeply involved in the pathophysiology of schizophrenia, particularly, positive symptoms. The nucleus accumbens receives glutamatergic inputs from a number of limbic areas, including the prefrontal cortex, hippocampus and amygdala, with most of its terminations occurring in the shell region (Shirayama and Chaki, 2006). The local injection of mGlu2/3 receptor agonists, such as LY354740 and LY379268, into the nucleus accumbens shell reduced dopamine release (Greenslade and Mitchell, 2004; Karasawa et al., 2006). Moreover, the local injection of LY379268 into the nucleus accumbens shell abolished the increase in dopamine release induced by the systemic administration of PCP (although the percentage of the increase induced by PCP did not change) in this region, while LY379268 did not affect dopamine release in the nucleus accumbens core (Greenslade and Mitchell, 2004). Therefore, the selective effect on dopamine release in this region may account for the antipsychotic effects of mGlu2/3 receptor agonists. The precise neuronal mechanisms underlying the regulation of dopamine release by the mGlu2/3 receptor is not fully understood. One possibility is the direct stimulation of mGlu2/3 receptors localized on dopaminergic terminals. However, mGlu2 and mGlu3 receptor mRNA are not expressed in the ventral tegmental area (Ohishi et al., 1993a,b), implying that the mGlu2/3 receptor is not presynaptic on dopaminergic terminals in the nucleus accumbens. In the shell, the terminals of glutamatergic afferents are in close apposition to dopaminergic afferents arising from the ventral tegmental area and form postsynaptic contacts with GABAergic spiny projection neurons. If limbic projections to the nucleus accumbens shell exert a facilitatory control on dopaminergic nerve terminals, stimulation of the mGlu2/3 receptor may reduce both basal and evoked dopamine release via an autoregulatory effect on glutamatergic transmission (Fig. 2). Indeed, a preferential mGlu2/3 receptor agonists, L-CGG-1, reportedly inhibited high K+-evoked dopamine release in the slices of nucleus accumbens, and this

Fig. 2. Proposed schema for the regulation of dopamine neuronal activity in the nucleus acumens shell. The nucleus accumbens shell receives glutamatergic inputs from the prefrontal cortex, hippocampus and amygdala. The terminals of glutamatergic afferents are in close apposition to the dopaminergic terminals from the ventral tegmental area. Thus, increased glutamate release in the nucleus accumbens shell may increase dopamine release, and the stimulation of mGlu2/3 receptors reduces the increase in glutamate release, which in turn reduces dopamine release.

63

response was attenuated by preferential mGlu2/3 receptor antagonists, such as MCCG and MTPG (Chaki et al., 2006), suggesting that mGlu2/3 receptor agonists may act within the nucleus accumbens. Moreover, the inhibitory effects of an mGlu2/3 receptor agonist were not abolished in the presence of tetrodotoxin (Chaki et al., 2006), indicating that the effect of an mGlu2/3 receptor agonist on dopamine release is unlikely to be mediated through interneurons. For reference, the systemic administration of LY354740 reportedly did not affect dopamine release induced by PCP in the nucleus accumbens (Moghaddam and Adams, 1998). Although the reason for this discrepancy remains to be elucidated, the local drug concentrations or the positioning of the probes may differ. In contrast to accumbal dopaminergic hyperactivity, a deficit in dopaminergic activity in the prefrontal cortex has been presumed to be related to working memory impairment and the negative symptoms of schizophrenia. This hypothesis stems from findings showing that dopamine depletion or the blockade of the D1 receptor in the prefrontal cortex impairs working memory in rhesus monkeys (Brozoski et al., 1979; Sawaguchi and Goldman-Rakic, 1994), and markers of dopamine axons were reduced in postmortem autopsies of the DLPFC in schizophrenic subjects (Akil et al., 1999). The systemic administration of LY379268 has been reported to increase dopamine release in the medial prefrontal cortex to the same extent as the effects of clozapine and risperidone, as determined using in vivo microdialysis studies (Cartmell et al., 2001). Increased dopamine release in the prefrontal cortex was observed when LY404039 was systemically administered (Rorick-Kehn et al., 2007). Interestingly, the local injection of LY379268 into the medial prefrontal cortex did not increase dopamine release, indicating that the site of action of LY379268 is located outside the medial prefrontal cortex. Although the precise neuronal mechanisms responsible for the mGlu2/3 receptor-mediated increase in prefrontal dopamine release is not fully understood, this effect might be involved in the effects of mGlu2/3 receptor agonists on cognitive dysfunction and the negative symptoms of schizophrenia. 4.3.3. Interaction with 5-HT2A receptor The blockade of the 5-HT2A receptor has been suggested to be involved in the action of atypical antipsychotics such as clozapine and risperidone. Accumulating evidence suggests that the 5-HT2A receptor interacts with the mGlu2 receptor both functionally and anatomically in the frontal cortex. A striking overlapping distribution of the mGlu2/3 receptor and the 5-HT2A receptor in the medial prefrontal cortex has been demonstrated using an autoradiography study with [3H] LY354740 as an mGlu2/3 receptor ligand and [125I](±)-1-(2,5dimethoxy-4-iodophenyl)-2-aminopropane (DOI) as a 5-HT2A receptor ligand (Marek et al., 2000). Marek et al. (2000) first demonstrated a functional interaction between the mGlu2/3 receptor and the 5-HT2A receptor by showing that LY354740 attenuated serotonin-induced excitatory postsynaptic currents (EPSCs) recorded in layer V pyramidal cells of the medial prefrontal cortex. Therefore, mGlu2/3 receptors negatively regulate 5-HT2A receptor-mediated responses to stimulate glutamate release, presumably from thalamocortical afferents to the prefrontal cortex (because thalamic lesions decreased both 5-HT2A receptor mediated EPSCs and mGlu2/3 receptor binding in the medial prefrontal cortex) (Marek et al., 2001) (Fig. 3A). Moreover, LY354740 suppressed head shakes induced by DOI in rats (Gewirtz and Marek, 2000), indicating that stimulation of the mGlu2/3 receptor behaviorally attenuates 5-HT2A receptor-mediated responses. Given that competitive and non-competitive NMDA receptor antagonists enhance the head twitch response in mice via 5-HT2A receptor activation (Kim et al., 1998), and that the administration of both hallucinogens (5-HT2A receptor agonists) and NMDA receptor antagonists in the presence of a hyperglutamatergic state (increased glutamate release) in the prefrontal cortex can cause psychotomimetic effects, the attenuation of the increase in glutamate release may be a common

64

S. Chaki / European Journal of Pharmacology 639 (2010) 59–66

Fig. 3. Proposed interaction between 5-HTergic and glutamatergic neurons in the prefrontal cortex. (A) Activity of glutamatergic thalamocortical afferents is presynaptically regulated by both mGlu2/3 receptors and 5-HT2A receptors. The stimulation of 5-HT2A receptors increases glutamate release, stimulating postsynaptic non-NMDA receptors to induce excitatory postsynaptic currents, while the stimulation of mGlu2/3 receptors reduces the increase in glutamate release as an autoreceptor. (B) Stimulation of 5-HT2A receptors induces two different signaling pathways, Gq/G11 mediated c-fos induction and Gi/Go mediated egr-2 induction in that egr-2 is only induced by hallucinogens. mGlu2 and 5-HT2A receptors may form a heterodimeric complex, and the stimulation of the mGlu2 receptor only prevents the 5-HT2A receptor-mediated hallucinogenic pathway.

mechanism of mGlu2/3 receptor agonists in alleviating behavioral abnormalities induced by both hallucinogens and NMDA receptor antagonists. Moreover, the inhibitory effects of an mGlu2/3 receptor agonist on 5-HT2A receptor-mediated EPSCs in the medial prefrontal cortex and 5-HT2A receptor agonist-induced head twitch were mimicked by a selective mGlu2 receptor potentiator, biphenylindanone A (Benneyworth et al., 2007). Therefore, the mGlu2 receptor, rather than the mGlu3 receptor, appears to be responsible for the effects of mGlu2/3 receptor agonists on 5-HT2A receptormediated responses. Recently, the 5-HT2A receptor and the mGlu2 receptor have been reported to form a heterodimeric complex involving the 4th and 5th transmembrane domain of mGlu2 receptors (González-Maeso et al., 2008). While both hallucinogenic 5-HT2A receptor agonists, such as DOI and lysergic acid diethylamide (LSD), and non-hallucinogenic 5HT2A receptor agonists, such as ergotamine, induce c-fos expression (which is mediated through Gq/G11), only hallucinogenic 5-HT2A receptor agonists induce egr-2, which is Gi/o dependent, in cortical neurons (González-Maeso et al., 2007). Thus, the 5-HT2A receptormediated induction of egr-2 may be a pathway selective for hallucinogens. Interestingly, LY379268 attenuated only the hallucinogen (DOI)-specific induction of egr-2 in both in vivo and in primary cortical cultures and did not attenuate c-fos induction by hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists (GonzálezMaeso et al., 2008) (Fig. 3B). In contrast, BINA, an mGlu2 receptor potentiator, reportedly attenuated (−)-DOB-induced Fos expression in the medial prefrontal cortex (Benneyworth et al., 2007), and LY379268 and LY566332, a selective mGlu2 receptor potentiator, reduced DOI-stimulated polyphosphoinositide hydrolysis in the frontal cortex in mice (Molinaro et al., 2009). The above-mentioned hypothesis remains to be confirmed. 5. Clinical results for mGlu2/3 receptor agonists To improve the low oral bioavailability of LY404039, an mGlu2/3 receptor agonist, Eli Lilly synthesized its pro-drug LY2140023 (a methionine amide of LY404039) and evaluated its efficacy in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blinded, placebo-controlled study (Patil et al., 2007). In this trial, a total of 196 patients were enrolled and randomly assigned according to a ratio of 3:2:1 to receive LY2140023, a placebo, or olanzapine for 4 weeks. Treatment with

LY2140023 (40 mg, b.i.d.) or olanzapine (15 mg, q.d.) for 4 weeks significantly improved the Positive and Negative Syndrome Scale (PANSS) scores (total, positive, negative) as well as the Clinical Global Impression-Severity (CGI-S) scores, compared with the placebo. The LY2140023 group, similar to the olanzapine group, showed a rapid onset of efficacy, with significant effects observed at 1 week and lasting for 4 weeks. After 4 weeks of treatment, the LY2140023 group showed a moderate decrease in body weight while the olanzapine group exhibited a significant increase in body weight. Moreover, LY2140023 neither increased prolactin nor worsened extrapyramidal symptoms. Based on these findings, mGlu2/3 receptor agonists may be effective and safe as a potential monotherapy for the treatment of schizophrenia, although larger and longer-term studies are needed. Although the impact of LY2140023 on cognitive dysfunction was not reported in the above study, LY354740 significantly and dosedependently improved working memory impairment, and modestly improved reduced vigilance and increased distractibility induced by ketamine infusion in 19 healthy volunteers, while LY354740 did not show significant effect on ketamine-induced verbal learning deficit and increased PANSS scores (Krystal et al., 2005).

6. Conclusion and future directions The recent results of a phase 2 clinical trial examining LY2140023, an mGlu2/3 receptor agonist, showed improvements in both positive and negative symptoms of schizophrenia, indicating that antipsychotics can effectively target the glutamate receptor and ignore direct interactions with dopamine systems. Importantly, patients taking LY2140023 did not show the typical side effects associated with medications targeting dopamine receptors, such as extrapyramidal syndroms or elevated serum prolactin levels; furthermore, unlike olanzapine, which has negative metabolic side effects such as weight gain, LY2140023 did not increase body weight (rather, it resulted in a loss of body weight). Therefore, mGlu2/3 receptor agonists might be superior to the antipsychotics currently used for the treatment of schizophrenia. Nevertheless, further studies are needed to solve a number of issues. LY2140023 was not as effective as olanzapine for the treatment of both positive and negative symptoms in the study, and the present study did not examine cognitive functions, which are poorly managed using the currently available antipsychotic medication. Larger clinical trials that include estimations of cognitive

S. Chaki / European Journal of Pharmacology 639 (2010) 59–66

dysfunction should provide important information on the utility of mGlu2/3 receptor agonists. As for the basic aspects of this new approach, the precise neuronal mechanisms by which mGlu2/3 receptor agonists exert their effects have not been fully elucidated. In particular, the role of the mGlu3 receptor remains to be elucidated. Other therapeutic opportunities for mGlu2/3 receptor agonists exist in addition to their possible use in the treatment of schizophrenia. These include anxiety (Palucha and Pilc, 2007), pain (Jones et al., 2005), epilepsy (Klodzinska et al., 2000), drug abuse (Helton et al., 1997; Vandergriff and Rasmussen, 1999), Parkinson's disease (Konieczny et al., 1998) and stroke (Bond et al., 2000); these opportunities are mostly based on the distribution of the receptors in the areas of interest for each disease, the involvement of glutamatergic transmission in these diseases, and the results of mGlu2/3 receptor agonists in experimental animal models. In particular, mGlu2/3 receptor agonists have been demonstrated their efficacy for anxiety not only in several animal models (Palucha and Pilc, 2007), but also in human anxiety models including panic disorder (Grillon et al., 2003; Kellner et al., 2005; Schoepp et al., 2003) and in patients with generalized anxiety disorder (Dunayevich et al., 2008). Therefore, mGlu2/3 receptor agonists could offer a new approach to the treatment of diseases in which the regulation of glutamatergic transmission may be effective. Moreover, investigating the neuronal mechanisms underlying the pharmacological effects of mGlu2/3 receptor agonists may unveil novel pathways for understanding the pathophysiology of diseases against which mGlu2/3 receptor agonists are effective. References Adams, B.W., Moghaddam, B., 2001. Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex. Biol. Psychiatry 50, 750–757. Akil, M., Pierri, J.N., Whitehead, R.E., Edgar, C.L., Mohila, C., Sampson, A.R., Lewis, D.A., 1999. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am. J. Psychiatry 156, 1580–1589. Aronica, E., Gorter, J.A., Ijlst-Keizers, H., Rozemuller, A.J., Yankaya, B., Leenstra, S., Troost, D., 2003. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur. J. Neurosci. 17, 2106–2118. Benneyworth, M.A., Xiang, Z., Smith, R.L., Garcia, E.E., Conn, P.J., Sanders-Bush, E., 2007. A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol. Pharmacol. 72, 477–484. Bond, A., Jones, N.M., Hicks, C.A., Whiffin, G.M., Ward, M.A., O'Neill, M.F., Kingston, A.E., Monn, J.A., Ornstein, P.L., Schoepp, D.D., Lodge, D., O'Neill, M.J., 2000. Neuroprotective effects of LY379268, a selective mGluR2/3 receptor agonist: investigation into possible mechanism of action in vivo. J. Pharmacol. Exp. Ther. 294, 800–809. Brown, E.M., Gamba, G., Ricardi, D., Lombardi, M., Butters, R., Kifor, O., Sun, A., Hediger, M.A., Lytton, J., Herbert, S.C., 1993. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 366, 575–580. Brozoski, T.J., Brown, R.M., Rosvold, H.E., Goldman, P.S., 1979. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205, 929–932. Bruno, V., Battaglia, G., Casabona, G., Copani, A., Caciagli, F., Nicoletti, F., 1998. Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta. J. Neurosci. 18, 9594–9600. Calcagno, E., Carli, M., Baviera, M., Invernizzi, R.W., 2009. Endogenous serotonin and serotonin2C receptors are involved in the ability of M100907 to suppress cortical glutamate release induced by NMDA receptor blockade. J. Neurochem. 108, 521–532. Cartmell, J., Monn, J., Schoepp, D.D., 2000. Attenuation of specific PCP-evoked behaviors by the potent mGluR2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine. Psychopharmacology 148, 423–429. Cartmell, J., Perry, K.W., Salhoff, C.R., Monn, J.A., Schoepp, D.D., 2001. Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade. Neuropharmacology 40, 847–855. Chaki, S., Yoshikawa, R., Okuyama, S., 2006. Group II metabotropic glutamate receptormediated regulation of dopamine release from slices of rat nucleus accumbens. Neurosci. Lett. 404, 182–186. Chen, Q., He, G., Chen, Q., Wu, S., Xu, Y., Feng, G., Li, Y., Wang, L., He, L., 2005. A casecontrol study of the relationship between the metabotropic glutamate receptor 3 gene and schizophrenia in the Chinese population. Schizophr. Res. 73, 21–26. Conn, P.J., Pin, J.P., 1997. Pharmacology and functions of metabotropic glutamate receptors. Ann. Rev. Pharmacol. Toxicol. 37, 205–237.

65

Conn, P.J., Lindsley, C.W., Jones, C.K., 2009. Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol. Sci. 30, 25–31. Corti, C., Crepaldi, L., Mion, S., Roth, A.L., Xuereb, J.H., Ferraguti, F., 2007. Altered dimerization of metabotropic glutamate receptor 3 in schizophrenia. Biol. Psychiatry 62, 747–755. Coyle, J.T., Tsai, G., 2004. The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology (Berl) 174, 32–38. Dudkin, K.N., Kruchinin, V.K., Chueva, I.V., 2001. Neurophysiological correlates of delayed visual differentiation tasks in monkeys: the effects of the site of intracortical blockade of NMDA receptors. Neurosci. Behav. Physiol. 31, 207–218. Dunayevich, E., Erickson, J., Levine, L., Landbloom, R., Schoepp, D.D., Tollefson, G.D., 2008. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology 33, 1603–1610. Egan, M.F., Straub, R.E., Goldberg, T.E., Yakub, I., Callicott, J.H., Hariri, A.R., Mattay, V.S., Bertolino, A., Hyde, T.M., Shannon-Weickert, C., Akil, M., Crook, J., Vakkalanka, R.K., Balkissoon, R., Gibbs, R.A., Kleinman, J.E., Weinberger, D.R., 2004. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 101, 12604–12609. Faustman, W.O., Bardgett, M., Faull, K.F., Pfefferbaum, A., Csernansky, J.G., 1999. Cerebrospinal fluid glutamate inversely correlates with positive symptom severity in unmedicated male schizophrenic/schizoaffective patients. Biol. Psychiatry 45, 68–75. Fell, M.J., Svensson, K.A., Johnson, B.G., Schoepp, D.D., 2008. Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (−)-(1R, 4S, 5S, 6S)-4amino-2-sulfonylbicyclo[3.1.0]hexane-4, 6-dicarboxylic acid (LY404039). J. Pharmacol. Exp. Ther. 326, 209–217. Fricker, A.C., Mok, M.H., de la Flor, R., Shah, A.J., Woolley, M., Dawson, L.A., Kew, J.N., 2009. Effects of N-acetylaspartylglutamate (NAAG) at group II mGluRs and NMDAR. Neuropharmacology 56, 1060–1067. Fujii, Y., Shibata, H., Kikuta, R., Makino, C., Tani, A., Hirata, N., Shibata, A., Ninomiya, H., Tashiro, N., Fukumaki, Y., 2003. Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia. Psychiatr. Genet. 13, 71–76. Galici, R., Echemendia, N.G., Rodriguez, A.L., Conn, P.J., 2005. A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J. Pharmacol. Exp. Ther. 315, 1181–1187. Gewirtz, J.C., Marek, G.J., 2000. Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23, 569–576. Geyer, M.A., Krebs-Thomson, K., Braff, D.L., Swerdlow, N.R., 2001. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156, 117–154. Ghose, S., Gleason, K.A., Potts, B.W., Lewis-Amezcua, K., Tamminga, C.A., 2009. Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action? Am. J. Psychiatry 166, 812–820. Gleason, S.D., Shannon, H.E., 1997. Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice. Psychopharmacology (Berl) 129, 79–84. González-Maeso, J., Weisstaub, N.V., Zhou, M., Chan, P., Ivic, L., Ang, R., Lira, A., BradleyMoore, M., Ge, Y., Zhou, Q., Sealfon, S.C., Gingrich, J.A., 2007. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53, 439–452. González-Maeso, J., Ang, R.L., Yuen, T., Chan, P., Weisstaub, N.V., López-Giménez, J.F., Zhou, M., Okawa, Y., Callado, L.F., Milligan, G., Gingrich, J.A., Filizola, M., Meana, J.J., Sealfon, S.C., 2008. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452, 93–97. Gozzi, A., Large, C.H., Schwarz, A., Bertani, S., Crestan, V., Bifone, A., 2008. Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. Neuropsychopharmacology 33, 1690–1703. Greenslade, R.G., Mitchell, S.N., 2004. Selective action of (-)-2-oxa-4-aminobicyclo [3.1.0]hexane-4, 6-dicarboxylate (LY379268), a group II metabotropic glutamate receptor agonist, on basal and phencyclidine-induced dopamine release in the nucleus accumbens shell. Neuropharmacology 47, 1–8. Grillon, C., Cordova, J., Levine, L.R., Morgan III, C.A., 2003. Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fearpotentiated startle paradigm in humans. Psychopharmacology (Berl) 168, 446–454. Harich, S., Gross, G., Bespalov, A., 2007. Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment. Psychopharmacology (Berl) 192, 511–519. Helton, D.R., Tizzano, J.P., Monn, J.A., Schoepp, D.D., Kallman, M.J., 1997. LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats. Neuropharmacology 36, 1511–1516. Henry, S.A., Lehmann-Masten, V., Gasparini, F., Geyer, M.A., Markou, A., 2002. The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology 43, 1199–1209. Higgins, G.A., Ballard, T.M., Kew, J.N., Richards, J.G., Kemp, J.A., Adam, G., Woltering, T., Nakanishi, S., Mutel, V., 2004. Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology 46, 907–917. Holcomb, H.H., Lahti, A.C., Medoff, D.R., Cullen, T., Tamminga, C.A., 2005. Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia. Neuropsychopharmacology 30, 2275–2282.

66

S. Chaki / European Journal of Pharmacology 639 (2010) 59–66

Imre, G., Fokkema, D.S., Ter Horst, G.J., 2006. Subchronic administration of LY354740 does not modify ketamine-evoked behavior and neuronal activity in rats. Eur. J. Pharmacol. 544, 77–81. Javitt, D.C., Zukin, S.R., 1991. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 148, 1301–1308. Jones, C.K., Eberle, E.L., Peters, S.C., Monn, J.A., Shannon, H.E., 2005. Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing. Neuropharmacology 49, 206–218. Karasawa, J., Yoshimizu, T., Chaki, S., 2006. A metabotropic glutamate 2/3 receptor antagonist, MGS0039, increases extracellular dopamine levels in the nucleus accumbens shell. Neurosci. Lett. 393, 127–130. Karasawa, J., Hashimoto, K., Chaki, S., 2008. D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav. Brain Res. 186, 78–83. Kaupmann, K., Huggel, K., Heid, J., Flor, P.J., Bischoff, S., Mickel, S.J., McMaster, G., Angst, C., Bittiger, H., Froestl, W., Bettler, B., 1997. Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors. Nature 386, 239–246. Kellner, M., Muhtz, C., Stark, K., Yassouridis, A., Arlt, J., Wiedemann, K., 2005. Effects of a metabotropic glutamate(2/3) receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results. Psychopharmacology (Berl) 179, 310–315. Kim, J.S., Kornhuber, H.H., Schmid-Burgk, W., Holzmüller, B., 1980. Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neurosci. Lett. 20, 379–382. Kim, H.S., Park, I.S., Park, W.K., 1998. NMDA receptor antagonists enhance 5-HT2 receptor-mediated behavior, head-twitch response, in mice. Life Sci. 63, 2305–2311. Klodzinska, A., Bijak, M., Chojnacka-Wojcik, E., Kroczka, B., Swiader, M., Czuczwar, S.J., Pilc, A., 2000. Roles of group II metabotropic glutamate receptors in modulation of seizure activity. Naunyn-Schmiedeberg's Arch. Pharmacol. 361, 283–288. Konieczny, J., Ossowska, K., Wolfarth, S., Plic, A., 1998. LY354740, a group II metabotropic glutamate receptor agonist with potential antiparkinsonian properties in rats. Naunyn Schmiedeberg's Arch. Pharmacol. 358, 500–502. Krystal, J.H., Abi-Saab, W., Perry, E., D'Souza, D.C., Liu, N., Gueorguieva, R., McDougall, L., Hunsberger, T., Belger, A., Levine, L., Breier, A., 2005. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl) 179, 303–309. Krystal, J.H., Karper, L.P., Seibyl, J.P., Freeman, G.K., Delaney, R., Bremner, J.D., Heninger, G.R., Bowers Jr., M.B., Charney, D.S., 1994. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 51, 199–214. Lahti, A.C., Weiler, M.A., Tamara Michaelidis, B.A., Parwani, A., Tamminga, C.A., 2001. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25, 455–467. Lewis, D.A., Gonzalez-Burgos, G., 2006. Pathophysiologically based treatment interventions in schizophrenia. Nat. Med. 12, 1016–1022. Lewis, D.A., Moghaddam, B., 2006. Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch. Neurol. 63, 1372–1376. Lorrain, D.S., Baccei, C.S., Bristow, L.J., Anderson, J.J., Varney, M.A., 2003. Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117, 697–706. Marek, G.J., Wright, R.A., Schoepp, D.D., Monn, J.A., Aghajanian, G.K., 2000. Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J. Pharmacol. Exp. Ther. 292, 76–87. Marek, G.J., Wright, R.A., Gewirtz, J.C., Schoepp, D.D., 2001. A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience 105, 379–392. Moghaddam, B., Adams, B.W., 1998. Reversal of phencyclidine effects by a group II metabotropic receptor agonists in rats. Science 281, 1349–1352. Mohn, A.R., Gainetdinov, R.R., Caron, M.G., Koller, B.H., 1999. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98, 427–436. Molinaro, G., Traficante, A., Riozzi, B., Di Menna, L., Curto, M., Pallottino, S., Nicoletti, F., Bruno, V., Battaglia, G., 2009. Activation of mGlu2/3 metabotropic glutamate receptors negatively regulates the stimulation of inositol phospholipid hydrolysis mediated by 5-HT2A serotonin receptors in the frontal cortex of living mice. Mol. Pharmacol. 76, 379–387. Nakanishi, S., 1992. Molecular diversity of glutamate receptors and implications for brain function. Science 258, 597–603. Nakanishi, S., Masu, M., 1994. Molecular diversity and functions of glutamate receptors. Ann. Rev. Biophys. Biomol. Struct. 23, 319–348. Nakazato, A., Kumagai, T., Sakagami, K., Yoshikawa, R., Suzuki, Y., Chaki, S., Ito, H., Taguchi, T., Nakanishi, S., Okuyama, S., 2000. Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. J. Med. Chem. 43, 4893–4909. Neale, J.H., Bzdega, T., Wroblewska, B., 2000. N-Acetylaspartylglutamate: the most abundant peptide neurotransmitter in the mammalian central nervous system. J. Neurochem. 75, 443–452.

Neale, J.H., Olszewski, R.T., Gehl, L.M., Wroblewska, B., Bzdega, T., 2005. The neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia. Trends Pharmacol. Sci. 26, 477–484. Neki, A., Ohishi, H., Kaneko, T., Shigemoto, R., Nakanishi, S., Mizuno, N., 1996. Pre- and postsynaptic localization of a metabotropic glutamate receptor, mGluR2, in the rat brain: an immunohistochemical study with a monoclonal antibody. Neurosci. Lett. 202, 197–200. Newcomer, J.W., Farber, N.B., Jevtovic-Todorovic, V., Selke, G., Melson, A.K., Hershey, T., Craft, S., Olney, J.W., 1999. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20, 106–118. Ohishi, H., Shigemoto, R., Nakanishi, S., Mizuno, N., 1993a. Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 53, 1009–1018. Ohishi, H., Shigemoto, R., Nakanishi, S., Mizuno, N., 1993b. Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J. Comp. Neurol. 335, 252–266. Olszewski, R.T., Wegorzewska, M.M., Monteiro, A.C., Krolikowski, K.A., Zhou, J., Kozikowski, A.P., Long, K., Mastropaolo, J., Deutsch, S.I., Neale, J.H., 2008. Phencyclidine and dizocilpine induced behaviors reduced by N-acetylaspartylglutamate peptidase inhibition via metabotropic glutamate receptors. Biol. Psychiatry 63, 86–91. Palucha, A., Pilc, A., 2007. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol. Ther. 115, 116–147. Patil, S.T., Zhang, L., Martenyi, F., Lowe, S.L., Jackson, K.A., Andreev, B.V., Avedisova, A.S., Bardenstein, L.M., Gurovich, I.Y., Morozova, M.A., Mosolov, S.N., Neznanov, N.G., Reznik, A.M., Smulevich, A.B., Tochilov, V.A., Johnson, B.G., Monn, J.A., Schoepp, D.D., 2007. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med. 13, 1102–1107. Pin, J.P., Duvoisin, R., 1992. The metabotropic glutamate receptors: structure and fuctions. J. Neurochem. 58, 1184–1186. Rorick-Kehn, L.M., Johnson, B.G., Knitowski, K.M., Salhoff, C.R., Witkin, J.M., Perry, K.W., Griffey, K.I., Tizzano, J.P., Monn, J.A., McKinzie, D.L., Schoepp, D.D., 2007. In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders. Psychopharmacology (Berl) 193, 121–136. Sartorius, L.J., Weinberger, D.R., Hyde, T.M., Harrison, P.J., Kleinman, J.E., Lipska, B.K., 2008. Expression of a GRM3 splice variant is increased in the dorsolateral prefrontal cortex of individuals carrying a schizophrenia risk SNP. Neuropsychopharmacology 33, 2626–2634. Sawaguchi, T., Goldman-Rakic, P.S., 1994. The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J. Neurophysiol. 71, 515–528. Schlumberger, C., Schäfer, D., Barberi, C., Morè, L., Nagel, J., Pietraszek, M., Schmidt, W.J., Danysz, W., 2009. Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition. Behav. Pharmacol. 20, 56–66. Schoepp, D.D., Conn, P.J., 1993. Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol. Sci. 14, 13–20. Schoepp, D.D., Wright, R.A., Levine, L.R., Gaydos, B., Potter, W.Z., 2003. LY354740, an mGlu2/ 3 receptor agonist as a novel approach to treat anxiety/stress. Stress 6, 189–197. Shimazaki, T., Kaku, A., Chaki, S., 2007. Blockade of the metabotropic glutamate 2/3 receptors enhances social memory via the AMPA receptor in rats. Eur. J. Pharmacol. 575, 94–97. Shirayama, Y., Chaki, S., 2006. Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents. Curr. Neuropharmacol. 4, 277–291. Takahashi, K., Tsuchida, K., Tanabe, Y., Masu, M., Nakanishi, S., 1993. Role of the large extracellular domain of metabotropic glutamate receptors in agonist selectivity determination. J. Biol. Chem. 268, 19341–19345. Takamori, K., Hirota, S., Chaki, S., Tanaka, M., 2003. Antipsychotic action of selective group II metabotropic glutamate receptor agonist MGS0008 and MGS0028 on conditioned avoidance responses in the rat. Life Sci. 73, 1721–1728. Tanabe, Y., Masu, M., Ishii, T., Shigemoto, R., Nakanishi, S., 1992. A family of metabotropic glutamate receptors. Neuron 8, 169–179. Tanabe, Y., Nomura, A., Masu, M., Shigemoto, R., Mizuno, N., Shigetada, N., 1993. Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. J. Neurosci. 13, 1372–1378. Tsai, G., Passani, L.A., Slusher, B.S., Carter, R., Baer, L., Kleinman, J.E., Coyle, J.T., 1995. Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch. Gen. Psychiatry 52, 829–836. Vandergriff, J., Rasmussen, K., 1999. The selective mGluR2/3 receptor antagonist LY354740 attenuates morphine- withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. Neuropharmacology 38, 217–222. Volk, D.W., Austin, M.C., Pierri, J.N., Sampson, A.R., Lewis, D.A., 2000. Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch. Gen. Psychiatry 57, 237–245.