ly-379268 and Schizophrenia

Prodromal memory deficits represent an important marker for the development of schizophrenia (SZ), in which glutamatergic hypofunction occurs in the prefrontal cortex (PFC). The mGluR2/3 agonist LY379268 (LY37) attenuates excitatory N-methyl-D-aspartate receptor (NMDAR)-induced neurotoxicity, a central pathological characteristic of glutamatergic hypofunction. We therefore hypothesized that early treatment with LY37 would rescue cognitive deficits and confer benefits for SZ-like behaviors in adults. To test this, we assessed whether early intervention with LY37 would improve learning outcomes in the Morris Water Maze for rats prenatally exposed to methylazoxymethanol acetate (MAM), a neurodevelopmental SZ model. We found that a medium dose of LY37 prevents learning deficits in MAM rats. These effects were mediated through postsynaptic mGluR2/3 via improving GluN2B-NMDAR function by inhibiting glycogen synthase kinase-3β (GSK3β). Furthermore, dendritic spine loss and learning and memory deficits observed in adult MAM rats were restored by juvenile LY37 treatment, which did not change prefrontal neuronal excitability and glutamatergic synaptic transmission in adult normal rats. Our results provide a mechanism for mGluR2/3 agonists against NMDAR hypofunction, which may prove to be beneficial in the prophylactic treatment of SZ.

Topics: Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Spines; Disease Models, Animal; Excitatory Amino Acid Agonists; Female; Glycogen Synthase Kinase 3 beta; Learning Disabilities; Methylazoxymethanol Acetate; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Schizophrenia; Tissue Culture Techniques

Elevated activity at the output stage of the anterior hippocampus has been described as a physiological endophenotype of schizophrenia, and its development maps onto the transition from the prodromal to the psychotic state. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia could be promising therapies. However, animal models with high construct validity to support such pre-clinical development are scarce. The Cyclin-D2 knockout (CD2-KO) mouse model shows a hippocampal parvalbumin-interneuron dysfunction, and its pattern of hippocampal over-activity shares similarities with that seen in prodromal patients. Conducting a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a rodent correlate of positive symptoms of schizophrenia), that was largely resistant against D1- and D2-dopamine-receptor antagonism, but responsive to the mGluR2/3-agonist LY379268. In the negative symptom domain, CD2-KO mice showed transiently reduced sucrose-preference (anhedonia), but enhanced interaction with novel mice and objects, as well as normal nest building and incentive motivation. Also, unconditioned anxiety, perseveration, and motor-impulsivity were unaltered. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, and also an impairment in working memory, that was resistant against LY379268-treatment. In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.

Topics: Amino Acids; Amphetamine; Animals; Attention; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Cognitive Dysfunction; Cyclin D2; Disease Models, Animal; Dopamine Antagonists; Exploratory Behavior; Hippocampus; Hyperkinesis; Male; Memory, Short-Term; Mice, Knockout; Motor Activity; Schizophrenia; Schizophrenic Psychology

An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.. We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.. Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions.. In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine.. We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.

Topics: Amino Acids; Animals; Antipsychotic Agents; Benzodiazepines; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nucleus Accumbens; Olanzapine; Phencyclidine; Prefrontal Cortex; Protein Binding; Receptors, GABA-A; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Recent heuristic models of schizophrenia propose that abnormalities in the gamma frequency cerebral oscillations may be closely tied to the pathophysiology of the disorder, with hypofunction of N-methyl-d-aspartate receptors (NMDAr) implicated as having a crucial role. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating that is disrupted in schizophrenia. We tested the ability for antipsychotic drugs with diverse pharmacological actions to (1) ameliorate NMDAr antagonist-induced disruptions to gamma oscillations and (2) attenuate NMDAr antagonist-induced disruptions to PPI. We hypothesized that antipsychotic-mediated improvement of PPI deficits would be accompanied by a normalization of gamma oscillatory activity. Wistar rats were implanted with extradural electrodes to facilitate recording of electroencephalogram during PPI behavioural testing. In each session, the rats were administered haloperidol (0.25 mg kg(-1)), clozapine (5 mg kg(-1)), olanzapine (5 mg kg(-1)), LY379268 (3 mg kg(-1)), NFPS (sarcosine, 1 mg kg(-1)), d-serine (1800 mg kg(-1)) or vehicle, followed by the NMDAr antagonists MK-801(0.16 mg kg(-1)), ketamine (5 mg kg(-1)) or vehicle. Outcome measures were auditory-evoked, as well as ongoing, gamma oscillations and PPI. Although treatment with all the clinically validated antipsychotic drugs reduced ongoing gamma oscillations, clozapine was the only compound that prevented the sensory-evoked gamma deficit produced by ketamine and MK-801. In addition, clozapine was also the only antipsychotic that attenuated the disruption to PPI produced by the NMDAr antagonists. We conclude that disruptions to evoked, but not ongoing, gamma oscillations caused by NMDAr antagonists are functionally relevant, and suggest that compounds, which restore sensory-evoked gamma oscillations may improve sensory processing in patients with schizophrenia.

Topics: Amino Acids; Animals; Antipsychotic Agents; Benzodiazepines; Bridged Bicyclo Compounds, Heterocyclic; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Electroencephalography; Haloperidol; Ketamine; Male; Olanzapine; Prepulse Inhibition; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia

Accumulating genetic evidence suggests that schizophrenia (SZ) is associated with individually rare copy number variations (CNVs) of diverse genes, often specific to single cases. However, the causality of these rare mutations remains unknown. One of the rare CNVs found in SZ cohorts is the duplication of Synaptic Scaffolding Molecule (S-SCAM, also called MAGI-2), which encodes a postsynaptic scaffolding protein controlling synaptic AMPA receptor levels, and thus the strength of excitatory synaptic transmission. Here we report that, in a transgenic mouse model simulating the duplication conditions, elevation of S-SCAM levels in excitatory neurons of the forebrain was sufficient to induce multiple SZ-related endophenotypes. S-SCAM transgenic mice showed an increased number of lateral ventricles and a reduced number of parvalbumin-stained neurons. In addition, the mice exhibited SZ-like behavioral abnormalities, including hyperlocomotor activity, deficits in prepulse inhibition, increased anxiety, impaired social interaction, and working memory deficit. Notably, the S-SCAM transgenic mice showed a unique sex difference in showing these behavioral symptoms, which is reminiscent of human conditions. These behavioral abnormalities were accompanied by hyperglutamatergic function associated with increased synaptic AMPA receptor levels and impaired long-term potentiation. Importantly, reducing glutamate release by the group 2 metabotropic glutamate receptor agonist LY379268 ameliorated the working memory deficits in the transgenic mice, suggesting that hyperglutamatergic function underlies the cognitive functional deficits. Together, these results contribute to validate a causal relationship of the rare S-SCAM CNV and provide supporting evidence for the rare CNV hypothesis in SZ pathogenesis. Furthermore, the S-SCAM transgenic mice provide a valuable new animal model for studying SZ pathogenesis.

Topics: Adaptor Proteins, Signal Transducing; Amino Acids; Animals; Anxiety; Bridged Bicyclo Compounds, Heterocyclic; DNA Copy Number Variations; Excitatory Postsynaptic Potentials; Female; Glutamic Acid; Guanylate Kinases; Locomotion; Long-Term Potentiation; Male; Maze Learning; Memory, Short-Term; Mice; Neurons; Parvalbumins; Phenotype; Prosencephalon; Receptors, AMPA; Schizophrenia; Sex Factors; Social Behavior; Up-Regulation

LY379268 and LY354740, two agonists of mGlu2/3 metabotropic glutamate receptors, display different potencies in mouse models of schizophrenia. This differential effect of the two drugs remains unexplained. We performed a proteomic analysis in cultured cortical neurons challenged with either LY379268 or LY354740. Among the few proteins that were differentially influenced by the two drugs, Rab GDP dissociation inhibitor-β (Rab GDIβ) was down-regulated by LY379268 and showed a trend to an up-regulation in response to LY354740. In cultured hippocampal neurons, LY379268 selectively down-regulated the α isoform of Rab GDI. Rab GDI inhibits the activity of the synaptic vesicle-associated protein, Rab3A, and is reduced in the brain of schizophrenic patients. We examined the expression of Rab GDI in mice exposed to prenatal stress ("PRS mice"), which have been described as a putative model of schizophrenia. Rab GDIα protein levels were increased in the hippocampus of PRS mice at postnatal days (PND)1 and 21, but not at PND60. At PND21, PRS mice also showed a reduced depolarization-evoked [(3)H]d-aspartate release in hippocampal synaptosomes. The increase in Rab GDIα levels in the hippocampus of PRS mice was reversed by a 7-days treatment with LY379268 (1 or 10 mg/kg, i.p.), but not by treatment with equal doses of LY354740. These data strengthen the validity of PRS mice as a model of schizophrenia, and show for the first time a pharmacodynamic difference between LY379268 and LY354740 which might be taken into account in an attempt to explain the differential effect of the two drugs across mouse models.

Topics: Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; D-Aspartic Acid; Disease Models, Animal; Epigenesis, Genetic; Female; Guanine Nucleotide Dissociation Inhibitors; Hippocampus; Male; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Proteomics; Receptors, Metabotropic Glutamate; Restraint, Physical; Schizophrenia

mGlu(2/3) receptor agonists were shown to possess an antipsychotic-like potential in animal studies. Recent clinical investigations revealed that their antipsychotic potential might also manifest in humans. LY379268, the group II mGlu receptor orthosteric agonist, was previously shown to exhibit antipsychotic-like action in animal models of schizophrenia. However, the mechanism of its action is not fully recognized. Here, we decided to investigate the involvement of 5-HT1A receptors in the LY379268-induced antipsychotic effects. We used models of positive, negative and cognitive symptoms of schizophrenia, such as MK-801- and amphetamine-induced hyperactivity tests, DOI-induced head twitches, social interaction and novel object recognition. LY379268 was active in a wide range of doses (0.5-5 mg/kg), depending on the paradigm. The effects of the drug were not antagonized by 5-HT(1A) antagonist, WAY100635 (0.1 mg/kg) in the models of positive and negative symptoms. Conversely, in the novel object recognition test, which exerts cognitive disturbances, the action of LY379268 was antagonized by WAY100635. Concomitantly, the action of a sub-effective dose of the drug was enhanced by the administration of a sub-effective dose of 5-HT(1A) agonist, (R)-(+)-8-Hydroxy-DPAT. Altogether, we propose that the antipsychotic-like action of group II mGlu receptors' agonist is 5-HT(1A) independent in context of positive and negative symptoms, while the action toward cognitive disturbances seems to be 5-HT(1A) dependent.

Topics: Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cognition; Dose-Response Relationship, Drug; Male; Mice; Motor Activity; Neuropsychological Tests; Piperazines; Pyridines; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Metabotropic Glutamate; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Social Behavior

Prenatal exposure to restraint stress causes long-lasting changes in neuroplasticity that likely reflect pathological modifications triggered by early-life stress. We found that the offspring of dams exposed to repeated episodes of restraint stress during pregnancy (here named 'prenatal restraint stress mice' or 'PRS mice') developed a schizophrenia-like phenotype, characterized by a decreased expression of brain-derived neurotrophic factor and glutamic acid decarboxylase 67, an increased expression of type-1 DNA methyl transferase (DNMT1) in the frontal cortex, and a deficit in social interaction, locomotor activity, and prepulse inhibition. PRS mice also showed a marked decrease in metabotropic glutamate 2 (mGlu2) and mGlu3 receptor mRNA and protein levels in the frontal cortex, which was manifested at birth and persisted in adult life. This decrease was associated with an increased binding of DNMT1 to CpG-rich regions of mGlu2 and mGlu3 receptor promoters and an increased binding of MeCP2 to the mGlu2 receptor promoter. Systemic treatment with the selective mGlu2/3 receptor agonist LY379268 (0.5 mg/kg, i.p., twice daily for 5 days), corrected all the biochemical and behavioral abnormalities shown in PRS mice. Our data show for the first time that PRS induces a schizophrenia-like phenotype in mice, and suggest that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress.

Topics: Amino Acids; Animals; Animals, Newborn; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Female; Male; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Metabotropic Glutamate; Restraint, Physical; Schizophrenia; Stress, Psychological

Current antipsychotics are ineffective at treating the negative and cognitive symptoms of schizophrenia, so there is a substantial need to develop more effective therapeutics for this debilitating disorder. The type II metabotropic glutamate receptor (mGluR2/3) is a novel, potential therapeutic target requiring evaluation in appropriate preclinical models of schizophrenia.. This study evaluated the potent, selective mGluR2/3 agonist, LY379268, on the behavioural deficits induced by rearing rat pups in social isolation from weaning, a neurodevelopmental model of schizophrenia, to investigate its antipsychotic potential.. Male Lister Hooded rats were weaned on post-natal day 23-25 and either group-housed (3-4 per cage) or isolation-reared for 6 weeks. At subsequent weekly intervals, animals received acute systemic injection of either vehicle or LY379268 (1 mg/kg; i.p.) 30 min prior to recording locomotor activity in a novel arena, novel object recognition, pre-pulse inhibition of acoustic startle and conditioned emotional response paradigms.. Isolation rearing induced locomotor hyperactivity, deficits in novel object recognition, conditioned emotional behaviour and attenuated the magnitude of the initial acoustic startle response in the PPI paradigm compared to that of group-housed controls. LY379268 reversed the isolation-induced locomotor hyperactivity, the object recognition deficit, and restored startle responses in isolated animals, whilst having no effect on conditioned emotional response impairments.. These data show that LY379268 can reverse some, but not all, post-weaning social isolation-induced changes which have translational relevance to core symptom defects in schizophrenia and support a potential therapeutic role of mGluR2/3 agonists in its treatment.

Topics: Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Male; Motor Activity; Rats; Receptors, Metabotropic Glutamate; Recognition, Psychology; Reflex, Startle; Schizophrenia; Social Isolation

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

Topics: Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cognition; Excitatory Amino Acid Agents; Male; Phencyclidine; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Schizophrenia; Time Factors; Xanthenes

Glutamatergic dysfunction is increasingly implicated in the pathophysiology of schizophrenia. Current models postulate that dysfunction of glutamate and its receptors underlie many of the symptoms in this disease. However, the mechanisms involved are not well understood. Although elucidating the role for glutamate transporters in the disease has been limited by the absence of pharmacological tools that selectively target the transporter, we recently showed that glial glutamate and aspartate transporter (GLAST; excitatory amino-acid transporter 1) mutant mice exhibit abnormalities on behavioral measures thought to model the positive symptoms of schizophrenia, some of which were rescued by treatment with either haloperidol or the mGlu2/3 agonist, LY379268 the mGlu2/3 agonist, LY379268. To further determine the role of GLAST in schizophrenia-related behaviors we tested GLAST mutant mice on a series of behavioral paradigms associated with the negative (social withdrawal, anhedonia), sensorimotor gating (prepulse inhibition of startle), and executive/cognitive (discrimination learning, extinction) symptoms of schizophrenia. GLAST knockout (KO) mice showed poor nesting behavior and abnormal sociability, whereas KO and heterozygous (HET) both demonstrated lesser preference for a novel social stimulus compared to wild-type littermate controls. GLAST KO, but not HET, had a significantly reduced acoustic startle response, but no significant deficit in prepulse inhibition of startle. GLAST KO and HET showed normal sucrose preference. In an instrumental visual discrimination task, KO showed impaired learning. By contrast, acquisition and extinction of a simple instrumental response was normal. The mGlu2/3 agonist, LY379268, failed to rescue the discrimination impairment in KO mice. These findings demonstrate that gene deletion of GLAST produces select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia.

Topics: Amino Acids; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cognition; Cognition Disorders; Disease Models, Animal; Excitatory Amino Acid Transporter 1; Female; Food Preferences; Learning; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Phenotype; Receptors, Metabotropic Glutamate; Reflex, Startle; Schizophrenia; Social Behavior Disorders; Sucrose

It has previously been reported that the glutamate ionotropic antagonist phencyclidine directly inhibits the release of prolactin in anterior pituitary cells in culture, suggesting that phencyclidine has a dopamine (DA)-like action on prolactin-releasing cells. It has also been reported that the glutamate metabotropic agonist LY379268 can stimulate the incorporation of [35S]GTP-gamma-S into DA D2Long receptors. The present study was done to examine whether such glutamatergic drugs had similar actions on the DA D2Short receptor. The present results show that phencyclidine, ketamine, and LY379268 also stimulated the incorporation of [35S]GTP-gamma-S into D2Short receptors. The proportion of D2Long and D2Short receptors existing in the high-affinity state were both markedly reduced by NaCl. While phencyclidine and LY379268 each stimulated the incorporation of GTP-gamma-S into D2Long and D2Short receptors, this stimulation was reduced by NaCl, with D2Short being much more sensitive than D2Long to the inhibition by NaCl. The binding of phencyclidine and LY379268 to D2High receptors in vivo was directly confirmed by the i.v. injection of phencyclidine and LY379268 in which 50% inhibited the binding of [3H]PHNO to the striatum ex vivo at 0.25 and 1.5 mg/kg, respectively. The results confirm that glutamate agonists and antagonists have a significant affinity for DA D2High receptors. The psychotogenic action of phencyclidine may stem from a combination or synergistic action of glutamate receptor antagonism and DA D2 agonism. In addition, the antipsychotic clinical action of LY379268 congeners such as LY404039 may be related to a combined or synergistic action of glutamate receptor stimulation together with a partial DA agonist action that reduces endogenous DA neurotransmission.

Topics: Amino Acids; Animals; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Corpus Striatum; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Humans; Phencyclidine; Protein Binding; Protein Isoforms; Rats; Receptors, Dopamine D2; Schizophrenia

Topics: Amino Acids; Antipsychotic Agents; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclic S-Oxides; Dopamine Agonists; Excitatory Amino Acid Agonists; Humans; Receptors, Dopamine D2; Schizophrenia

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 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], an ortho-steric mGlu2/3 receptor agonist, induced similar dose-dependent 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.

Topics: Allosteric Regulation; Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds, Heterocyclic; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Kinetics; Male; Mice; Mice, Inbred C57BL; Motor Activity; Predictive Value of Tests; Pyridines; Receptors, Metabotropic Glutamate; Reflex, Acoustic; Schizophrenia; Sulfonamides

Group II mGlu receptor agonists (eg LY379268 and LY354740) have been shown to reverse many of the behavioral responses to PCP as well as glutamate release elicited by PCP and ketamine. In the present set of experiments, we used in vivo microdialysis to show that, in addition to reversing PCP- and ketamine-evoked glutamate release, group II mGlu receptor stimulation also prevents ketamine-evoked norepinephrine (NE) release. Pretreating animals with the mixed 2/3 metabotropic glutamate (mGlu2/3) receptor agonist LY379268 (0.3-10 mg/kg) dose-dependently inhibited ketamine (25 mg/kg)-evoked NE release in the ventral hippocampus (VHipp). Ketamine hyperactivity was also reduced in a similar dose range. Following our initial observation on NE release, we conducted a series of microinjection experiments to reveal that the inhibitory effects of LY379268 on VHipp NE release may be linked to glutamate transmission within the medial prefrontal cortex. Finally, we were able to mimic the inhibitory effects of LY379268 on ketamine-evoked NE release by using a novel mGlu2 receptor selective positive modulator. (+/-) 2,2,2-Trifluoroethyl [3-(1-methyl-butoxy)-phenyl]-pyridin-3-ylmethyl-sulfonamide (2,2,2-TEMPS, characterized through in vitro GTPgammaS binding) at a dose of 100 mg/kg significantly reduced the NE response. Together, these results demonstrate a novel means to suppress noradrenergic neurotransmission (ie by activating mGlu2 receptors) and may, therefore, have important implications for neuropsychiatric disorders in which aberrant activation of the noradrenergic system is thought to be involved.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acids; Analysis of Variance; Animals; Area Under Curve; Binding Sites; Bridged Bicyclo Compounds, Heterocyclic; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Guanosine 5'-O-(3-Thiotriphosphate); Hippocampus; Humans; Hyperkinesis; In Vitro Techniques; Ketamine; Male; Microdialysis; Motor Activity; Norepinephrine; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Metabotropic Glutamate; Schizophrenia; Serotonin; Sulfur Isotopes; Time Factors; Trifluoroethanol; Xanthenes

Previous work has shown that mGlu2/3 receptor agonists such as LY379268 inhibit motor responses to acutely administered phencyclidine (PCP) in rats. However, it has not been determined whether mGlu2/3 receptor agonists will reverse the enhanced effects of repeatedly administered PCP (so called PCP sensitization). In these studies, rats were administered daily PCP and monitored for the number of ambulations, fine movements, time at rest and rears using an automated activity system. At Day 10, when compared the first (Day 1) response, PCP-treated animals showed enhanced responses to all measures tested. Augmentations of these PCP-induced behaviors generally peaked between the third and tenth day after PCP administration had begun. Acute administration of LY379268 effectively suppressed PCP-evoked motor behaviors in rats sensitized to PCP. However, daily administrations of LY379268 (for 9 days), along with PCP, did not prevent the expression of the enhanced PCP response on Day 10. Thus, LY379268 administration can suppress PCP responses after either acute or chronic exposure to PCP. However, the underlying plasticity that leads to PCP sensitization was not affected by this treatment.

Topics: Amino Acids; Animals; Brain; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Male; Membranes; Motor Activity; Phencyclidine; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Schizophrenia