LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine

159

155

Recent studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2/3) have potential utility as novel therapeutic agents for treatment of psychiatric disorders such as anxiety and schizophrenia. Agonists of mGlu2/3 receptors block amphetamine-and phencyclidine (PCP)-induced hyperlocomotor activity in rodents, two actions that may predict potential antipsychotic activity of these compounds. We now report that LY487379 [N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine], a recently described selective allosteric potentiator of mGlu2 receptor, has behavioral effects similar to mGlu2/3 receptor agonists. LY487379 and LY379268 [(Ϫ)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], an ortho-steric mGlu2/3 receptor agonist, induced similar dosedependent reductions in PCP-and amphetamine-induced hyperlocomotor activity in C57BL6/J mice at doses that did not significantly alter spontaneous locomotor activity. These effects were blocked by the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid]. LY487379 had a short duration of action compared with LY379268. Furthermore, unlike the mGlu2/3 agonist, LY487379 reversed amphetamine-induced disruption of prepulse inhibition of the acoustic startle reflex. When LY379268 was given chronically, it failed to block amphetamine-and PCP-induced hyperlocomotor activity. The finding that the effects of an orthosteric mGlu2/3 receptor agonist in these models can be mimicked by a selective allosteric potentiator of mGlu2 suggests that these effects are mediated by the mGlu2 receptor subtype. Furthermore, these data raise the possibility that a selective allosteric potentiator of mGlu2 receptor could have utility as a novel approach for the treatment of schizophrenia.

Section: Discussionsupporting

confidence: 92%

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

Galici

Echemendia²,

Rodriguez³

et al. 2005

159

155

“…The AMPA/kainate-selective antagonist LY293558 attenuated PCP-evoked locomotion only in ␣-MPT-treated animals, whereas the 5-HT 2A/2C selective antagonist ketanserin blocked PCP-induced behaviors in both control and ␣-MPTtreated (but not PCPA-treated) subjects. Despite reports that have indicated that group II mGlu receptor agonists are unable to affect some discriminative and sensorimotor gating properties associated with PCP administration (Schreiber et al, 2000), these data support the hypothesis that group II mGlu agonists represent a novel therapeutic approach to the treatment of schizophrenia.…”

Section: Discussioncontrasting

confidence: 48%

The Group II Metabotropic Glutamate Receptor Agonist (−)-2-Oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) and Clozapine Reverse Phencyclidine-Induced Behaviors in Monoamine-Depleted Rats

Swanson

Schoepp

2002

Recent studies have indicated that the selective group II metabotropic glutamate (mGlu) receptor agonist (Ϫ)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) shares common biochemical and pharmacological effects with the atypical antipsychotic clozapine. The present study aimed to further investigate these similarities (or differences) in monoamine-depleted animals by using the phencyclidine (PCP) model. Animals were pretreated 24 h before PCP administration with (i.p.) vehicle, ␣-methyl-DL-p-tyrosine methyl ester (␣-MPT; 400 mg/kg), or DL-pchlorophenyl-alanine methyl ester (PCPA; 300 mg/kg) injections. ␣-MPT and PCPA pretreatment significantly and selectively reduced catecholamine (dopamine and norepinepherine) or 5-hydroxytryptamine (5-HT, serotonin) and 5-hydroxyindoleacetic acid levels, respectively, in whole brain tissue. Both LY379268 and clozapine (s.c.) blocked PCP-evoked ambulatory activity and fine movements in control, ␣-MPT-, and PCPA-treated animals. In contrast, the typical antipsychotic haloperidol (s.c.) attenuated PCP behaviors in control and PCPA-pretreated animals, but was without effect in subjects pretreated with ␣-MPT. The ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate-selective antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)OH-tetrazole-6-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) attenuated locomotor activity in ␣-MPT-treated animals only, whereas the 5-HT 2A/2C -selective antagonist ketanserin was effective at reducing ambulations and fine movements in control and ␣-MPTtreated animals. Taken together, these data indicate an important role for glutamatergic and serotonergic mechanisms for PCP-evoked behaviors in catecholamine-depleted animals and suggest that like clozapine, LY379268 is more effective than typical antipsychotics in these models. This study further supports the potential use of group II mGlu agonists as novel therapeutic agents in the treatment of schizophrenia.

“…Although enhanced glutamate release, hyperlocomotion, and stereotypy elicited by PCP were blocked by LY354740 (Moghaddam and Adams, 1998), improving effects of mGluR2/3 agonists on PCP-induced PPI disruption were limited (Schreiber et al, 2000;Henry et al, 2002;Galici et al, 2005Galici et al, , 2006. At present, we could not explain why mGluR2/3 agonists only reversed hyperlocomotion and stereotypy elicited by PCP but not PPI disruption.…”

Section: F B Cmentioning

confidence: 67%

Unique Antipsychotic Activities of the Selective Metabotropic Glutamate Receptor 1 Allosteric Antagonist 2-Cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one

Satow

Suzuki²,

Maehara³

et al. 2009

A newly discovered metabotropic glutamate receptor (mGluR) 1 allosteric antagonist, 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one (CFMTI), was tested both in vitro and in vivo for its pharmacological effects. CFMTI demonstrated potent and selective antagonistic activity on mGluR1 in vitro and in vivo after oral administration. CFMTI inhibited L-glutamate-induced intracellular Ca 2ϩ mobilization in Chinese hamster ovary cells expressing human and rat mGluR1a, with IC 50 values of 2.6 and 2.3 nM, respectively. The selectivity of CFMTI to mGluR1 over mGluR5 was Ͼ2000-fold, and CFMTI at 10 M showed no agonistic or antagonistic activities toward other mGluR subtypes and other receptors. It antagonized face-washing behavior in mice induced by (S)-3,5-dihidroxyphenylglycine at a dose range of 3 to 30 mg/kg, for which receptor occupancy was 73 to 94%. As with the classical neuroleptic haloperidol and an atypical antipsychotic, clozapine, orally administered CFMTI reduced methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition (PPI) at the same dose range as required to antagonize the face-washing behavior. CFMTI and clozapine improved ketamine-induced hyperlocomotion, PPI disruption and (5S,10R)-(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-induced social withdrawal without any cataleptogenic activities, whereas haloperidol only improved ketamineinduced hyperlocomotion. CFMTI, unlike clozapine, caused neither hypolocomotion nor motor incoordination at therapeutic doses. In c-fos expression studies, CFMTI and clozapine increased the number of fos-positive neurons in the nucleus accumbens and medial prefrontal cortex but not in the dorsolateral striatum. These results suggest that the antipsychotic activities of mGluR1 antagonists are more similar to those of atypical antipsychotics than those of typical antipsychotics.L-Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and acts on both ligand-gated ion channels (ionotropic glutamate receptors; iGluRs) and G protein-coupled metabotropic glutamate receptors (mGluRs). The mGluR family consists of eight recep-A.S. and G.S. contributed equally to this work. Article, publication date, and citation information can be found at