Metabotropic glutamate receptor targets for neuropsychiatric disorders

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Vol. 3, No. 4 2006

Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY

TODAY THERAPEUTIC

STRATEGIES

Nervous system disorders

Metabotropic glutamate receptor targets for neuropsychiatric disorders Anni-Maija Lindena, Darryle D. Schoeppb,* a

Institute of Biomedicine, Pharmacology, University of Helsinki, 00014 Helsinki, Finland Neuroscience Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, drop code 0510, Indianapolis, IN 46285, USA

b

The actions of glutamate in the synapse are modulated by metabotropic glutamate (mGlu) receptors (mGlu18) that are expressed on nerve terminals, post-synaptic sites and glia. Recently, new positive and negative orthosteric or allosteric modulators for mGlu receptor

Section Editors: David Sibley – National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA C. Anthony Altar – Psychiatric Genomics, Gaithersburg, USA Theresa Branchek – Lundbeck Research, Paramus, USA

groups or subtypes have been discovered allowing for pharmacological studies in animal models and early clinical investigations. Evidence indicates that mGlu2/ 3 receptor agonists and mGlu5 receptor antagonists may be useful to treat anxiety and drug abuse disorders, whereas mGlu2/3 agonists have activity in certain psychosis models. Interestingly, potentiators of mGlu5 receptors might enhance cognition or treat negative symptoms in schizophrenia, whereas antagonists for mGlu2/3 receptors have activity in models of depression. Comparatively, less is known about the potential role of modulating other mGlu receptors (mGlu1, 4, 7, and 8) in psychiatric disorders; however, progress has been made with less selective agents and transgenic animal tools, suggesting that other novel approaches are on the horizon. Introduction A disturbed balance of excitatory and inhibitory neurotransmission has been implicated in almost all central nervous system disorders. Here we review recent findings that indicate *Corresponding author: D.D. Schoepp ([email protected]) 1740-6773/$ ß 2006 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ddstr.2006.10.018

metabotropic glutamate (mGlu) receptors as potential targets for treatment of anxiety, schizophrenia, depression and addiction (Fig. 1). We focus on preclinical studies demonstrating activity of mGlu receptor ligands in behavioral and neurochemical animal models of these psychiatric disorders. The effects of glutamate are mediated through ion channel receptors and through G-protein-coupled mGlu receptors. mGlu receptors consist of eight subtypes that can be divided into three groups based on their molecular structure, signal transduction and pharmacological profile [1–3]. Group I mGlu receptors (mGlu1 and mGlu5) are coupled via Gq to phospholipase C and phosphoinositide hydrolysis. They are not only primarily localized in postsynaptic neurons where they positively modulate neuronal excitability but are also found in presynaptic terminals and glial cells (mGlu5 receptor). Group II (mGlu2 and mGlu3) and group III (mGlu4, mGlu6, mGlu7 and mGlu8) mGlu receptors are coupled via Gi to adenylyl cyclase and inhibit stimulated cAMP formation. They are not only predominantly localized in presynaptic neurons where they function as inhibitory autoreceptors but are also found in postsynaptic neurons and glial cells (mGlu3 receptor). Localization in specific cellular compartments (e.g. synaptic versus perisynaptic) and different regional distribution of mGlu receptors indicates that each subtype has a unique role, modulating 507

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Figure 1. Metabotropic glutamate receptor (mGluR) approaches to normalize pathological imbalances in glutamatergic function for therapeutic benefit. Brain excitability is controlled by the balance of excitatory glutamate inputs and inhibitory GABA (g-aminobutyric acid) inputs on post-synaptic cells. Decreases in excitatory glutamate function (glutamate hypofunction) have been linked to depressive symptoms and disrupted cognition such as that associated with Schizophrenia. Thus drugs that increase glutamatergic function in key synapses and brain areas, such as mGluR2/3 antagonists and mGluR5 potentiators, are potential new approaches to treating these conditions of glutamate hypofunction. Increases in excitatory glutamate function (glutamate hyperfunction) have been linked to anxiety disorders, drug abuse, and psychosis (due to limbic disinhibition such as that associated with Schizophrenia). Thus drugs that decrease glutamatergic hyperfunction in key synapses and brain areas, such as mGluR2/3 agonists and mGluR5 antagonists, are potential new approaches to treating these conditions of glutamate hyperfunction. The overall goal is to normalize or dampen pathology changes in brain excitability, with minimal effects on normal processes in the brain. Metabotropic glutamate receptors, as indirect modulators of glutamate excitability with selective distributions in the CNS are considered as promising new drug targets in this regard. Several animal model studies and some early clinical studies have also validated these approaches (see Tables 1–4).

neuronal excitability in physiological and pathological processes in the central nervous system. To discuss mechanisms of how activation or inhibition of certain mGlu receptors leads to behavioral effects is beyond the scope of this article. Pharmacology of mGlu receptors has been evolved from group-selective orthosteric amino-acid-based agonists and antagonists and, more recently, from allosteric modulators that are often highly specific for a single subtype owing to a less conserved binding site within the transmembrane region compared with the extracellular glutamate binding site (for review see [4]). The most studied negative modulators are 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogs inhibiting mGlu5 receptors. Also, several antagonists [(e.g. (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine hydrochloride (LY456236), 3-ethyl-2methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) and 3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone (JNJ16259685)] for mGlu1 receptors have been developed. Positive modulators have been synthesized for mGlu1 [(S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476)], mGlu2 [e.g. N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine (MPPTS or LY487379), N-[40 -cyano-biphenyl-3-yl)-N-(3pyridinylmethyl)-ethanesulfonamide hydrochloride (CBiPES), 30 -[[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl]biphenyl-4-carboxylic aci (BINA)], mGlu4 [(-)-N-phenyl-7-(hydroxyimino) cyclopro508

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pa[b]chromen-1a-carboxamide (PHCCC)], mGlu5 [3-cyanoN-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB)] and mGlu7 [N,N’-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082)] receptors. So far, few in vivo behavioral studies have been performed with these positive allosteric modulators, but early studies suggest therapeutic potential in preclinical animal models for anxiety and psychosis.

mGlu receptors in anxiety-related disorders Increasing evidence from preclinical and early clinical studies suggests that negative modulation of glutamate signaling via mGlu receptors is a promising approach to treat anxiety [5]. One approach is to reduce glutamate transmission by inhibiting group I mGlu receptor activity, particularly targeting mGlu5 receptors using the non-competitive antagonist MPEP [6]. Systemically active and potent non-competitive antagonists MPEP and its analog 3-[2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) have shown anxiolytic activity in several rat and mouse anxiety tests (Table 1). The role for mGlu5 receptors in modulation of fear/stress responses is further confirmed by the phenotype of mGlu5 receptor knockout mice showing attenuated stress-induced hyperthermia [7]. Anxiolytic activity of non-competitive antagonists for mGlu1 receptors is less consistent (Table 1). Local injections of MPEP suggest that inhibition of mGlu5 receptors in the hippocampus and amygdala may mediate reduced anxiety behavior [8,9].

mGlu receptor

Compound (administration) a

b

c

Agonist/antagonist

Observation/effect

Refs

mGlu1

LY456236 (i.p. ) EMQMCM (i.p.) JNJ16259685d (i.p.)

Noncompetitive antagonist

Anxiolytic activity in mouse stress-induced hyperthermia, rat fear potentiated startle, conditioned freezing and lick suppression tests; no effect in rat elevated plus maze, zero maze or Geller–Seifter tests.

[26,64,65]

mGlu5

MPEPe (i.p., s.c.f, p.og.) MTEPh (i.p., p.o.) Fenobam (p.o.)

Noncompetitive antagonist

Anxiolytic activity in rat Vogel drinking test, rat fear-potentiated startle, and rat conditioned ultrasonic vocalization, mouse stress-induced hyperthermia and mouse four-plate test; decreased the number of buried marbles in mouse anxiety test; increased contact time in rat social exploration test. Inconsistent results in rat elevated plus maze and rat Geller–Seifter tests.

References for MPEP, see [5]. [26,66,67]

MPEP (central)

Intrahippocampal injection produced anticonflict effect in rat Vogel drinking test

[8]

MPEP (central)

Intra-amygdaloid injection produced anxiolytic effects in rat elevated plus maze, light-dark and shock-probe burying tests.

[9]

mGlu5/mouse

Reduced stress-induced hyperthermia

[7]

Group II

i

Agonist

Reduced fear-potentiated startle in healthy humans and reduced CO2-induced panic anxiety in humans; LY544344 improved symptoms of generalized anxiety disorder patients; chronic treatment of panic patients with LY354740 did not differ from placebo.

[10–13]

LY354740 (i.p., s.c., p.o.)

Agonist

Anxiolytic activity in elevated plus maze, mouse stress-induced hyperthermia, rat fear-potentiated startle, rat conflict drinking test and mouse four-plate test; prevented lactate-induced panic response in panic-prone rats.

[5]

LY354740 (central)

Agonist

Intrahippocampal injection produced anticonflict effect in rat Vogel drinking test

[8]

LY354740 (central)

Agonist

Intra-amygdaloid injection reduced fear-potentiated startle in rats

[16]

LY354740 (s.c.)

Agonist

Reduced stress-induced c-Fos in the mouse hippocampus and increased c-Fos in the extended central amygdala

[17]

4-MPPTSj 4-APPESk CBiPESl BINAm (i.p., s.c.)

Positive modulator

Anxiolytic activity in rat fear-potentiated startle, mouse stress-induced hyperthermia, mouse elevated plus maze tests

[26,43,44]

mGlu2 / mouse

Abolished anxiolytic activity of LY354740 in elevated plus maze test; abolished LY354740-induced c-Fos in the extended central amygdala.

[15,18]

mGlu2 / mouse

Hyperlocomotion in novel environment, but anxiety-related behavior not altered

[62]

mGlu3

mGlu3 / mouse

Abolished anxiolytic activity of LY354740 in elevated plus maze test; increased c-Fos expression in the hippocampus.

[15,18]

Group III

L-SOPn ACPT-Io HomoAMPAp (central)

Agonist

Intrahippocampal injections produced anticonflict effects in rat Vogel drinking test

[8,68]

MSOPq (central)

mGlu2

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509

Antagonist

Intrahippocampal injection produced anticonflict effect in rat Vogel drinking test

[19]

mGlu4

r

PHCCCp (central)

Positive modulator

Intra-amygdaloid injection produced anticonflict effect in rat Vogel drinking test

[20]

mGlu7

s

Positive modulator

Increased plasma corticosterone and corticotropin levels

[21]

Deficits in conditioned fear response and taste aversion, reduced anxiety behavior in elevated plus maze, light-dark box and staircase tests, and reduced stress-induced hyperthermia; dysregulation of hypothalamic–pituitary–adrenal axis.

[22–24]

AMN082 (p.o.) mGlu7 / mouse

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LY354740 (p.o.) LY544344 (prodrug of LY354740, p.o.)

Vol. 3, No. 4 2006

Table 1. Select studies implicating mGlu receptors as potential targets for anxiety disorders

mGlu8 / mouse

(4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine hydrochloride. Intraperitoneal. c 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate. d 3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone. e 2-methyl-6-(phenylethynyl)pyridine. f Subcutaneous. g Oral. h 3-[2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine. i (1S,2S,5R,6S)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid. j N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine. k N-[4-(4-carboxamidophenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride monohydrate. l N-[40 -cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride). m 0 3 -[[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl]biphenyl-4-carboxylic acid. n L-serine-O-phosphate. o (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid. p 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid. q (RS)-a-methylserine-O-phosphate. r ()-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide. s N,N0 -dibenzhydrylethane-1,2-diamine dihydrochloride. t (S)-3,4-decarboxyphenylglycine. b

Increased anxiety behavior in elevated plus maze test

[25] a

[26,69] Reduced stress-induced hyperthermia in mice; intrahippocampal or amygdaloid injections had no anticonflict effect in rats. Agonist (S)-3,4-DCPG (i.p., central) mGlu8

Observation/effect Agonist/antagonist Compound (administration) mGlu receptor

Table 1 (Continued ) 510

t

Refs

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Another approach to reduce anxiety via mGlu receptors is to activate group II mGlu receptors. In the human population, the systemically active, selective and potent mGlu2/3 receptor agonist (1S,2S,5R,6S)-2-aminobicyclo [3.1.0]hexane2,6-dicarboxylic acid (LY354740) reduced CO2-induced anxiety in panic disorder patients [10], had anxiolytic effects in the fear-potentiated startle paradigm in normal volunteers [11] and treated generalized anxiety disorder when administered in its prodrug form to increase oral bioavailability (LY544344) [12]. However, LY354750 did not reduce the number of panic attacks in panic patients receiving chronic treatment [13]. In animals, an initial finding of the anxiolytic activity of LY354740 [14] has been later repeated in several other rodent anxiety tests (Table 1). Similar results have been obtained using different type of mGlu2 receptor potentiators (Table 1) suggesting the mGlu2 receptor-mediated mechanism. However, the activation of both mGlu2 and mGlu3 receptors is required for LY354740 to produce anxiolytic behavior in the elevated plus maze test, because separate deletions of mGlu2 or mGlu3 receptors abolished the anxiolytic actions of LY354740 [15]. Activation of mGlu2/3 receptors in the hippocampus and amygdala may mediate anxiolysis because direct injections of mGlu2/3 receptor agonists in these regions produced anxiolytic-like behaviors [8,16]. Indeed, an anxiolytic dose of LY35470 reduced stress-induced c-Fos expression in the mouse hippocampus [17]. Moreover, the abolished anxiolytic activity of LY354740 in mGlu2 knockout mice was associated with the abolished LY354740-induced c-Fos expression in the central amygdala and bed nucleus of stria terminalis, and the abolished anxiolysis of LY35740 in mGlu3 knockout mice may be related to enhanced neuronal activity in the knockout hippocampus as suggested by increased c-Fos expression levels [18]. Compared with group I and II receptors, less is known about group III mGlu receptors in regulation of fear behaviors, partly owing to the lack of selective and systemically active agonists and antagonists. Not only intrahippocampal injections of the group III agonist L-serine-O-phosphate (L-SOP) but also the antagonist (RS)-a-methylserine-O-phophate (MSOP) have been reported to produce anticonflict effects in the rat Vogel drinking test [8,19]. Two recently synthesized positive modulators indicate mGlu4 and mGlu7 receptors in regulation of fear behaviors. A positive modulator for mGlu4 produced anticonflict effects in the rat Vogel drinking test when injected directly in the amygdala [20], and a positive modulator for mGlu7 has been reported to increase corticosterone and corticotrophin levels after oral administration, but no data are available of its actions in preclinical anxiety tests [21]. The phenotype of mGlu7 receptor knockout mouse suggests that inhibition of mGlu7 receptors maybe beneficial in anxiety disorders because knockout mice exhibited anxiolytic-like activity in several behavioral tests

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Table 2. Select studies implicating mGlu receptors as potential targets for depression and mood disorders mGlu receptor

Compound (administration) a

Agonist/antagonist

Observation/effect

Refs

mGlu1

EMQMCM (i.p.)

Noncompetitive antagonist

Antidepressant effects in rat forced swim and mouse tail suspension tests

[30]

mGlu5

MPEPb MTEPc (i.p.)

Noncompetitive antagonist

Shortened immobility time in a mouse tail suspension test, but inconsistent effects in a rat forced swim test; chronic treatment restored behavioral deficits of bulbectomized rats.

[30-32]

Group II

LY379268d (i.p.)

Agonist

Co-administration of low doses shortened the time required for neuroadaptation to imipramine (down-regulation of beta-adrenergic receptors) in mice

[70]

LY341495e (i.p.)

Antagonist

Co-administration shortened the time for neuroadaptation to imipramine in mice

[70]

MGS0039f LY341495 (i.p.)

Antagonist

Antidepressant effects in mouse tail suspension and rat forced swim tests; repeated dosing reduced learned helplessness in rats; repeated dosing increased cell proliferation in the mouse dentate gyrus.

[33,71,72]

Shorter immobility time in forced-swim test but not in tail-suspension test

[62]

Antidepressant effects in a rat forced-swim test after intracerebroventricular administration

[68]

Antidepressant effects in forced-swim and tail suspension tests; dysregulation of hypothalamic-pituitary-adrenal axis; increased mRNA expression of the brain-derived neurotrophic factor in the hippocampus.

[23,24]

mGlu2 / mouse Group III

ACPT-Ig RS-PPGh (i.c.v.)i

mGlu7

mGlu7 / mouse

Agonist

a

3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate. 2-methyl-6-(phenylethynyl)pyridine. c 3-[2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine. d ()-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid. e (aS)-a-amino-a-[(1S,2S)-2-carboxycyclopropyl]-9H-xanthene-9-propanoic acid. f Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. g (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid. h (RS)-4-phosphonophenylglycine. i Intracerebroventricular. b

(Table 1) [22,23]. However, mGlu7 deletion also disturbed the function of hypothalamic-pituitary-adrenal axis [24]. In contrast to mGlu7 receptor knockout mice, the knockout of mGlu8 receptors increased anxiety-like behaviors on the elevated plus maze [25]. Supporting the role of mGlu8 receptor activation in controlling fear responses, systemic administration of the potent and selective mGlu8 receptor agonist (S)-3,4-decarboxyphenylglycine ((S)-3,4-DCPG) reduced stress-induced hyperthermia [26]. Interestingly, the opposite anxiety phenotypes of mGlu7 and mGlu8 receptor knockout mice indicate different functions for these two predominantly presynaptic group III mGlu receptors in mediating and processing fear responses.

mGlu receptors in depression Several lines of evidence suggest that modulation of glutamatergic neurotransmission has antidepressant actions [27]. Also mGlu receptors are implicated, as mGlu receptors have been shown to undergo adaptive changes after treatment with clinically used antidepressants. For example, chronic antidepressant or electroconvulsive shock treatments alter

the expression and function of mGlu1, 5 and 2/3 receptors in the rat forebrain, especially in the hippocampus [28,29]. However, relatively few behavioral studies have been performed to test antidepressant actions of mGlu receptor ligands (Table 2). Reducing glutamate signaling by inhibiting group I mGlu receptors maybe beneficial, as the non-competitive antagonist for mGlu1 receptors, EMQMCM, reduced immobility time in rat forced swim test and mouse tail-suspension test [30], and also the mGlu5 receptor antagonist MPEP had antidepressant-like activity in the mouse tail suspension, although not in the rat forced swim test [31]. Chronic MPEP treatment restored learning deficits of bulbectomized rats, suggesting the efficacy of mGlu5 receptor inhibition in this model of depression [32]. On the contrary, enhancing glutamate signaling by antagonizing mGlu2/3 receptors also shows antidepressant-like effects, as potent and specific antagonists for mGlu2/3 receptors, amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (aS)-a-amino-a[(1S,2S)-2-carboxycyclopropyl]-9H-xanthene-9-propanoic www.drugdiscoverytoday.com

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Table 3. Select studies implicating mGlu receptors as potential targets for psychotic disorders mGlu receptor

Compound (administration)

Agonist/ antagonist

Observation/effect

Refs

mGlu1

EMQMCMa (i.p.b)

Noncompetitive antagonist

No effect on MK-801-induced locomotor activity or disruption of prepulse inhibition of acoustic startle in rats

[73]

Deficits in prepulse inhibition of acoustic startle; enhanced amphetamineinduced motor responses.

[35,59]

mGlu1 / mouse mGlu5

CHPGc (i.c.v.d)

Agonist

Reversed amphetamine-induced disruption of prepulse inhibition in rats

[36]

CDPPBe (s.c.f)

Positive modulator

Reversed amphetamine-induced disruption of prepulse inhibition and amphetamine-induced hyperlocomotion in rats

[37]

MPEPg (i.p.)

Noncompetitive antagonist

Reduced amphetamine-induced hyperlocomotion in mice

[38]

MPEP MTEPh (i.p.)

Noncompetitive antagonist

Potentiated phencyclidine- and MK-801-induced locomotor activity and disruption of prepulse inhibition in rats

[36,73]

Deficits in prepulse inhibition of acoustic startle

[36]

mGlu5 / mouse Group II

mGlu2

i

LY354740 (p.o.)

Agonist

Alleviated ketamine-induced working memory disruptions in healthy human subjects

[39]

LY354740 LY379268j (i.p., s.c.)

Agonist

Suppressed phencyclidine- and MK-801-induced behaviors in rats; suppressed phencyclidine-induced glutamate release and MK-801-induced changes in neuronal responding in the rat prefrontal cortex.

[45,48,74]

LY354740 (i.p.)

Agonist

Failed to attenuate phencyclidine-induced disruption of prepulse inhibition in rats

[41]

LY379268 (i.p., central)

Agonist

Systemic, cortical or thalamic injections decreased neuronal injury in the rat retrosplenial cortex produced by MK-801.

[47]

LY354740 LY379268 (i.p.)

Agonist

Suppressed hallucinogen DOI-induced behaviors in rats and c-fos mRNA expression in the rat medial prefrontal cortex

[46,75]

MGS0008k MGS0028l (p.o.)

Agonist

Produced antipsychotic effect by reducing conditioned avoidance response in rats

[76]

BINAm (i.p.)

Positive modulator

Reversed phencyclidine-induced locomotor activity and disruption of prepulse inhibition in mice; no effect on amphetamine-induced locomotor activity.

[44]

LY487379 CBiPESn (i.p.)

Positive modulator

Reversed amphetamine-induced locomotor activity and amphetamine-disrupted prepulse inhibition in mice

[42,43]

Abolished inhibitory activity of LY314582 (racemic LY354740) on phencyclidine-induced behaviors

[40]

Phencyclidine-induced behaviors reversed in rats by inhibition of glutamate carboxypeptidase II, an enzyme deactivating mGlu3 specific endogenous neuropeptide N-acetylaspartylglutamate (NAAG)

[51]

Alterations in activity of the glutamate carboxypeptidase II in the hippocampus of schizophrenic patients

[52]

Genetic polymorphisms associated with schizophrenia; a single nucleotide polymorphism affects glutamate transmission in the prefrontal cortex.

[50]

mGlu2/ mouse mGlu3

ZJ43 (i.p.)

a

Enzyme inhibitor

3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate. Intraperitoneal. 2-chloro-5-hydroxyphenylglycine. d Intracerebroventricular. e 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide. f Subcutaneous. g 2-methyl-6-(phenylethynyl)pyridine. h 3-[2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine. i (1S,2S,5R,6S)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid. j ()-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid. k 5-[2-[4-(6-fluoro-1H-indole-3-yl) piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide. l (1R, 2S, 5S, 6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate. m 0 3 -[[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl]biphenyl-4-carboxylic acid. n N-[4’-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride). b c

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acid (LY341495) decrease immobility time or learned helplessness in mouse and rat tests (Table 2). Repeated dosing of MGS0039 also increased cell proliferation in the mouse dentate gyrus, which is a common effect for clinically effective antidepressant drugs [33]. Recently, Cryan et al. [21] reported that mGlu7 receptor knockout mice exhibited reduced immobility time in the tail suspension and forced swim tests, indicating that the inactivation of this group III receptor may produce antidepressant effects in addition to the anxiolytic effects mentioned above. Moreover, mGlu7 receptor knockout mice have enhanced expression levels of the brain-derived neurotrophic factor in the hippocampus [24], suggesting enhanced hippocampal glutamatergic activity and supporting a phenotype with mood enhancing properties as seen in behavioral studies.

mGlu receptors in psychosis and schizophrenia Because of the psychotomimetic effects of non-competitive NMDA receptor antagonists such as phencyclidine, dizocilpine (MK-801) and ketamine, altered glutamate neurotransmission is thought to underlie the pathophysiology of schizophrenia [34]. There is some evidence that group I mGlu receptors may play a role in neuronal pathways affected in schizophrenia. Inhibition of the group I mGlu receptors appears to enhance psychotic symptoms induced by psychotomimetic drugs (non-competitive NMDA receptor antagonists and amphetamine) and disrupt prepulse inhibition, which suggests similar deficiencies in processing sensory information as observed in schizophrenic patients (Table 3). Also, both mGlu1 and mGlu5 receptor knockout mice display impaired prepulse inhibition [35,36]. Consistent with these results, both agonist, and positive modulators for the mGlu5 receptor reversed amphetamine-induced behaviors [36,37]. However, inhibition of mGlu5 receptors by systemic MPEP can also reverse amphetamine-induced hyperlocomotion in mice, thus the role of mGlu5 receptors in psychosis models based on behaviors produced by amphetamine administration remains unclear [38]. A recent study on healthy human volunteers showed that the mGlu2/3 agonist LY354740 alleviated ketamine-induced deficits in working memory although not the other effects of ketamine [39]. Consistently, selective and potent mGlu2/3 agonists also show antipsychotic actions in several rodent models used to test potential antipsychotic drugs (Table 3). At least some of the antipsychotic actions of mGlu2/3 agonists appear to be mediated via activation of the mGlu2 receptors because phencyclidine-induced behaviors were not inhibited by LY314582 (racemic LY354740) in mGlu2 receptor knockout mice, although inhibited in wild-type mice [40]. Moreover, recently developed selective positive modulators of mGlu2 receptors reversed phencyclidine- and amphetamine-induced behaviors (Table 3). Interestingly, positive

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modulators of the mGlu2 receptors also reversed the amphetamine- or phencyclidine-disrupted prepulse inhibition in mice, whereas the mGlu2/3 agonist LY354740 did not in an earlier rat study [41-44]. The site and mechanism of antipsychotic action of mGlu2/3 agonists remain hypothetical, but systemic or locally applied mGlu2/3 agonists appear to inhibit the actions of psychotomimetic drugs especially in the medial prefrontal cortex [45–48]. Several genetic studies indicate that polymorphisms of the mGlu3 receptor are associated with schizophrenia or with the outcome of treatment with the antipsychotic drug, olanzapine (for references, see [49]). Interestingly, a single nucleotide polymorphism in the mGlu3 gene was shown to affect glutamate transmission in the prefrontal cortex [50]. There is also other evidence that the mGlu3 receptor-mediated mechanisms maybe important in pathophysiology of schizophrenia. For example, phencyclidine-induced behaviors were reversed when the levels of a specific endogenous mGlu3 receptor agonist, neuropeptide N-acetylaspartylglutamate, were increased by treating animals with a specific enzyme inhibitor [51]. Moreover, the activity of the same enzyme that deactivates N-acetylaspartylglutamate maybe altered in the schizophrenic brain [52]. The role of mGlu3 in glutamate neurotransmission has so far been difficult to separate from the actions of mGlu2, as relatively little is known about mGlu3 functioning in pre- and postsynaptic neurons and glial cells. However, increasing evidence suggests its role in glutamate signaling in the brain regions affected in schizophrenia.

mGlu receptors in addiction Pharmacological studies with ligands for mGlu receptors suggest the importance of modulation of glutamatergic neurotransmission in different steps during development of addiction (for a review, see [53]). For example, chronic use of cocaine or withdrawal from morphine has been shown to produce alterations in the expression and function of mGlu receptors and associated Homer proteins in several brain regions (e.g. [54,55]). Earlier studies using brain injections have also shown that development of dependence for morphine was inhibited by group I, II and III antagonists if they were given chronically together with morphine, suggesting the importance of mGlu receptor activity [56]. More recent behavioral studies with subtype selective ligands are discussed below (Table 4). Until recently, little was known about the role of mGlu1 receptors in addiction. However, it has now been shown that systemic activation of mGlu1 receptors using the selective enhancer Ro 67-7476 can reverse cocaine-induced changes in glutamate signaling on dopamine neurons in the ventral tegmental area [57]. Earlier, cocaine self-administration has been reported to reduce the inhibition mediated by group I mGlu receptors in the same neurons [58]. These results www.drugdiscoverytoday.com

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Table 4. Select studies implicating mGlu receptors as potential targets for addiction mGlu Compound receptor (administration) mGlu1

Agonist/ antagonist

Observation/effect

Refs

CPCCOEta (i.p.)b

Noncompetitive antagonist

No effect on ethanol reward, place-conditioning and consumption in alcohol-preferring rats

[77]

Ro 67-7476c (i.p.)

Positive modulator Reversed cocaine-induced synaptic plasticity in the rat ventral tegmental dopamine neurons

mGlu1 / mouse mGlu5

Enhanced amphetamine-induced motor responses

[59]

MPEPd (i.p.)

Noncompetitive antagonist

Increased thresholds of intracranial self-stimulation in rats.

[61]

MPEP (i.p., i.v.)

Noncompetitive antagonist

Reduced cocaine self-administration, drug-induced seeking and effects on discriminative stimulus in monkeys; reduced the development of conditioned place preference for cocaine in mice and cocaine self-administration in rats; reduced locomotor stimulatory effects of cocaine in mice.

[38,78,79]

MPEP (i.p.)

Noncompetitive antagonist

Reduced amphetamine-induced hyperlocomotion in mice

[38]

MPEP (i.p.)

Noncompetitive antagonist

Inhibited the development and expression of conditioned place preference for morphine in mice

[80]

MPEP (i.p., i.v.)

Noncompetitive antagonist

Reduced nicotine self-administration in rats and mice and nicotine-induced drug seeking behavior in rats, but no effect on the nicotine-induced potentiation of brain stimulation reward in rats

[61,78,81]

MPEP MTEPe (i.p., s.c.f)

Noncompetitive antagonist

Reduced ethanol seeking behavior and ethanol deprivation effect in rats; reduced ethanol consumption in alcohol-preferring rats; reduced ethanol consumption in mice.

[77,82–84]

Lack of self-administration of cocaine and cocaine-induced locomotor activity

[60]

Increased thresholds of intracranial self-stimulation in rats

[61]

mGlu5 / mouse Group II LY314582 Agonist (racemic LY354740g; i.p.)

mGlu2

LY379268h (s.c., i.p.)

Agonist

Reduced cocaine- and food-seeking behaviors in rats

[85,86]

LY379268 (i.p.)

Agonist

Reduced self-administration of amphetamine enhanced by previous exposure in rats

[87]

LY379268 LY404039 (i.p.) Agonist

Reduction of ethanol self-administration and reinstatement in rats required doses that reduced also spontaneous locomotor activity; reduced ethanol seeking and relapse behavior but not self-administration in alcohol-preferring rats.

[88,89]

LY314582 (racemic LY354740; i.p.)

No effect on nicotine-induced potentiation of brain stimulation reward in rats

[61]

mGlu8

Agonist

LY354740 (p.o.)

Agonist

Attenuated enhanced auditory startle caused by nicotine withdrawal in rats

[90]

LY354740 (i.p., s.c.)

Antagonist

Inhibited symptoms of morphine withdrawal in mice and rats; suppressed activation of the rat locus coeruleus by morphine withdrawal.

[63,91]

MCCGi (i.c.v.)j

Antagonist

Chronic administration attenuated the development of morphine dependence in rats

[56]

mGlu2 / mouse

Group III MAP4k (i.c.v.) mGlu4

Enhanced cocaine-conditioned place preference and sensitization after chronic treatment [62] Antagonist

mGlu4 / mouse l

(S)-3,4-DCPG (i.p.)

a

Agonist

Chronic administration attenuated the development of morphine dependence in rats.

[56]

Lack of motor stimulatory effect of ethanol

[92]

Reduction of ethanol self-administration and reinstatement in rats required doses that reduced also spontaneous locomotor activity

[88]

7-(hydroxyimino)cyclopropan[b]chromen-1alpha-carboxylic ethyl ester. Intraperitoneal. c (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine. d 2-methyl-6-(phenylethynyl)pyridine. e 3-[2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine. f Subcutaneous. g (1S,2S,5R,6S)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid. h ()-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid. i (2S, 10 S, 20 S)-2-methyl-2-(2-carboxycyclopropyl)glycine. j Intracerebroventricular. k a-methyl-L-amino-4-phosphonobutanoate. l (S)-3,4-decarboxyphenylglycine. b

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suggest that pharmacological activation of the mGlu1 receptors may alleviate addictive actions of psychostimulants by reversing their actions on the ventral tegmental dopamine neurons, although direct behavioral evidence still lacks. Consistently with this mechanism, mGlu1 receptor knockout mice showed enhanced responses to stimulatory actions of amphetamine [59]. In contrast to the mGlu1 receptors, the deletion or inhibition of the mGlu5 receptors appears to inhibit the actions of psychostimulants (Table 4), although also the activation of the mGlu5 receptors may inhibit certain actions of amphetamine [36,37] (Table 3). Nevertheless, the mGlu5 receptor knockout mice do not self-administrate cocaine or show cocaine-induced locomotor activity [60]. Consistently, the mGlu5 receptor antagonist MPEP reduced cocaine selfadministration and several cocaine-induced behaviors in monkeys, rats or mice (Table 4). Systemic administration of MPEP or MTEP has also been shown to attenuate selfadministration or rewarding effects of other abused drugs such as morphine, nicotine and ethanol (Table 4). Systemic administration of an mGlu2/3 receptor agonist increased the threshold for intracranial self-stimulation in rats, suggesting that group II mGlu receptors can control glutamatergic activity in reward pathways [61]. Moreover, in several behavioral tests, systemic administration of mGlu2/3 agonists reduces rewarding effects of cocaine and also ethanol (Table 4). Consistently, mGlu2 receptor knockout mice showed increased conditioned place preference and sensitization after chronic cocaine [62]. Several studies have implicated mGlu2/3 receptors in regulation of withdrawal symptoms (Table 4). Activation of mGlu2/3 receptors and thus increased inhibition of glutamate release in the locus coeruleus appears to attenuate morphine withdrawal symptoms [63]. Lack of selective and systemically active ligands for group III receptors has hindered studies to elucidate their role in addiction (Table 4).

Conclusions Preclinical studies reveal intriguing observation that sometimes both activation and inhibition of the same receptors produce potentially therapeutic effects. For example, the agonists for mGlu2/3 receptors show prominent anxiolytic activity whereas the antagonists for mGlu2/3 receptors produce potentially antidepressant effects. Overall, recent preclinical studies clearly demonstrate that the mGlu receptors are very promising targets for several neuropsychiatric disorders. The anxiolytic activity of both mGlu5 receptor antagonist MPEP and mGlu2/3 receptor agonist LY354740 are especially well established in preclinical animal models and LY354740 also in human population. Accumulating evidence suggests that mGlu2/3 receptor agonists or mGlu5 potentiators may be effective ways for treatment of psychosis and schizophrenia. Positive modulation of mGlu1 receptors

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may be a promising, but yet untested way to reverse addictive actions of psychostimulants. Also, the inhibition of mGlu5 receptors and activation of mGlu2/3 receptors appear to attenuate various effects of abused drugs. Still, very little is known about the role of mGlu4, 7, and 8 (group III) or mGlu3 receptors per se in psychiatric disorders, but rapid advances in the pharmacology of this area may soon shed light on these targets as well.

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