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1.  Neuropetide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala 
Neuron  2008;59(2):298-310.
Summary
A deficient extinction of memory is particularly important in the regime of fear, where it limits the beneficial outcomes of treatments of anxiety disorders. Fear extinction is thought to involve inhibitory influences of the prefrontal cortex on the amygdala, although the detailed synaptic mechanisms remain unknown. Here we report that neuropeptide S (NPS), a recently discovered transmitter of ascending brainstem neurons, evokes anxiolytic effects and facilitates extinction of conditioned fear responses when administered into the amygdala in mice. An NPS receptor antagonist exerts functionally opposing responses, indicating that endogenous NPS is involved in anxiety behavior and extinction. Cellularly, NPS increases glutamatergic transmission to intercalated GABAergic neurons in the amygdala via presynaptic NPS receptors on connected principal neurons. These results identify mechanisms of NPS in the brain, a key role of intercalated neurons in the amygdala for fear extinction, and a potential pharmacological avenue for treating anxiety disorders.
doi:10.1016/j.neuron.2008.07.002
PMCID: PMC2610688  PMID: 18667157
2.  The Glycine Transporter-1 Inhibitor SSR103800 Displays a Selective and Specific Antipsychotic-like Profile in Normal and Transgenic Mice 
Neuropsychopharmacology  2009;35(2):416-427.
Schizophrenia has been initially associated with dysfunction in dopamine neurotransmission. However, the observation that antagonists of the glutamate N-methyl--aspartate (NMDA) receptor produce schizophrenic-like symptoms in humans has led to the idea of a dysfunctioning of the glutamatergic system via its NMDA receptor. As a result, there is a growing interest in the development of pharmacological agents with potential antipsychotic properties that enhance the activity of the glutamatergic system via a modulation of the NMDA receptor. Among them are glycine transporter-1 (GlyT1) inhibitors such as SSR103800, which indirectly enhance NMDA receptor function by increasing the glycine (a co-agonist for the NMDA receptor) levels in the synapse. This study aimed at investigating the potential antipsychotic-like properties of SSR103800, with a particular focus on models of hyperactivity, involving either drug challenge (ie, amphetamine and MK-801) or transgenic mice (ie, NMDA Nr1neo−/− and DAT−/−). Results showed that SSR103800 (10–30 mg/kg p.o.) blocked hyperactivity induced by the non-competitive NMDA receptor antagonist, MK-801 and partially reversed spontaneous hyperactivity of NMDA Nr1neo−/− mice. In contrast, SSR103800 failed to affect hyperactivity induced by amphetamine or naturally observed in dopamine transporter (DAT−/−) knockout mice (10–30 mg/kg p.o.). Importantly, both classical (haloperidol) and atypical (olanzapine, clozapine and aripiprazole) antipsychotics were effective in all these models of hyperactivity. However, unlike these latter, SSR103800 did not produce catalepsy (retention on the bar test) up to 30 mg/kg p.o. Together these findings show that the GlyT1 inhibitor, SSR103800, produces antipsychotic-like effects, which differ from those observed with compounds primarily targeting the dopaminergic system, and has a reduced side-effect potential as compared with these latter drugs.
doi:10.1038/npp.2009.144
PMCID: PMC3055391  PMID: 19759529
antipsychotic; NMDA receptor; dopamine transporter; GlyT1; SSR103800; schizophrenia
3.  Glutamatergic Dysbalance and Oxidative Stress in In Vivo and In Vitro Models of Psychosis Based on Chronic NMDA Receptor Antagonism 
PLoS ONE  2013;8(7):e59395.
Background
The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists in healthy humans and their tendency to aggravate psychotic symptoms in schizophrenic patients have promoted the notion of altered glutamatergic neurotransmission in the pathogenesis of schizophrenia.
Methods
The NMDA-receptor antagonist MK-801 was chronically administered to rats (0.02 mg/kg intraperitoneally for 14 days). In one subgroup the antipsychotic haloperidol (1 mg/kg) was employed as a rescue therapy. Glutamate distribution and 3-NT (3-nitrotyrosine) as a marker of oxidative stress were assessed by immunohistochemistry in tissue sections. In parallel, the effects of MK-801 and haloperidol were investigated in primary embryonal hippocampal cell cultures from rats.
Results
Chronic NMDA-R antagonism led to a marked increase of intracellular glutamate in the hippocampus (126.1 +/− 10.4% S.E.M of control; p = 0.037), while 3-NT staining intensity remained unaltered. No differences were observed in extrahippocampal brain regions. Essentially these findings could be reproduced in vitro.
Conclusion
The combined in vivo and in vitro strategy allowed us to assess the implications of disturbed glutamate metabolism for the occurrence of oxidative stress and to investigate the effects of antipsychotics. Our data suggest that oxidative stress plays a minor role in this model than previously suggested. The same applies to apoptosis. Moreover, the effect of haloperidol seems to be mediated through yet unidentified mechanisms, unrelated to D2-antagonism. These convergent lines of evidence indicate that further research should be focused on the glutamatergic system and that our animal model may provide a tool to explore the biology of schizophrenia.
doi:10.1371/journal.pone.0059395
PMCID: PMC3711936  PMID: 23869202
4.  Age-related differential sensitivity to MK-801-induced locomotion and stereotypy in C57BL/6 mice 
European journal of pharmacology  2007;580(1-2):161-168.
Psychomotor effects elicited by systemic administration of the noncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 (dizocilpine maleate) represent perturbation of glutamatergic pathways, providing an animal model for psychotic symptoms of schizophrenia. Hyperlocomotion and stereotypy are the two main psychomotor behaviors induced by MK-801. This study compared MK-801-induced hyperlocomotion and stereotypy in young (1-month old) and aged mice (12-month old), in order to determine how the aging process may influence these behaviors. The tested MK-801 doses ranged from 0.015 to 1 mg/kg. The data indicated that MK-801 impacted the aged mice more pronouncedly than the young mice, as both hyperlocomotion and stereotypy were increased significantly more in the aged mice relative to the young mice. These results suggest an age-related increase in MK-801 sensitivity in mice.
doi:10.1016/j.ejphar.2007.07.071
PMCID: PMC2705961  PMID: 18053981
Noncompetitive NMDA receptor antagonist; Dizocilpine maleate; Locomotion; Stereotypy; Aging; Differential drug sensitivity
5.  Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice 
Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.
doi:10.1016/j.ntt.2012.07.007
PMCID: PMC3509253  PMID: 22898204
amphetamine; autism; ethanol withdrawal; repetitive behavior; social approach; stereotypy
6.  The Role of NMDA Receptor Antagonists in Nicotine Tolerance, Sensitization, and Physical Dependence: A Preclinical Review 
Yonsei Medical Journal  2008;49(2):175-188.
Nicotine, the primary psychoactive component of tobacco products, produces diverse neurophysiological, motivational, and behavioral effects through several brain regions and neurochemical pathways. Various neurotransmitter systems have been explored to understand the mechanisms behind nicotine tolerance, dependence, and withdrawal. Recent evidence suggests that glutamate neurotransmission has an important role in this phenomenon. The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation.
doi:10.3349/ymj.2008.49.2.175
PMCID: PMC2615322  PMID: 18452252
Nicotine; NMDA receptors; tolerance; sensitization dependence
7.  Postnatal BDNF Expression Profiles in Prefrontal Cortex and Hippocampus of a Rat Schizophrenia Model Induced by MK-801 Administration 
Neonatal blockade of N-methyl-D-aspartic acid (NMDA) receptors represents one of experimental animal models for schizophrenia. This study is to investigate the long-term brain-derived neurotrophic factor (BDNF) expression profiles in different regions and correlation with “schizophrenia-like” behaviors in the adolescence and adult of this rat model. The NMDA receptor antagonist MK801 was administered to female Sprague-Dawley rats on postnatal days (PND) 5 through 14. Open-field test was performed on PND 42, and PND 77 to examine the validity of the current model. BDNF protein levels in hippocampus and prefrontal cortex (PFC) were analyzed on PND 15, PND 42, and PND 77. Results showed that neonatal challenge with MK-801 persistently elevated locomotor activity as well as BDNF expression; the alterations in BDNF expression varied at different developing stages and among brain regions. However, these findings provide neurochemical evidence that the blockade of NMDA receptors during brain development results in long-lasting alterations in BDNF expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia. Further study in the mechanisms and roles of the BDNF may lead to better understanding of the pathophysiology of schizophrenia.
doi:10.1155/2010/783297
PMCID: PMC2896884  PMID: 20625416
8.  Clonidine and guanfacine attenuate phencyclidine-induced dopamine overflow in rat prefrontal cortex: Mediating influence of the alpha-2A adrenoceptor subtype 
Brain research  2008;1246:41-46.
N-methyl-D-aspartic acid/glutamate receptor antagonists induce psychotomimetic effects in humans and animals, and much research has focused on the neurochemical and network-level effects that mediate those behavioral changes. For example, a reduction in NMDA-dependent glutamatergic transmission triggers increased release of the monoamine transmitters, and some of these changes are implicated in the cognitive, behavioral and neuroanatomical effects of phencyclidine (PCP). Alpha-2 adrenoceptor agonists (e.g., clonidine) are effective at preventing many of the behavioral, neurochemical and anatomical effects of NMDA antagonists. Evidence has indicated that a key mechanism of the clonidine-induced reversal of the effects of NMDA antagonists is an attenuation of enhanced dopamine release. We have pursued these findings by investigating the effects of alpha-2 agonists on PCP-evoked dopamine efflux in the prefrontal cortex of freely moving rats. Clonidine (0.003–0.1 mg/kg, i.p.) dose-dependently attenuated the ability of PCP (2.5 mg/kg, i.p.) to increase cortical dopamine output. The effects of clonidine were prevented by the alpha-2A subtype selective antagonist BRL-44408 (1 mg/kg, i.p.). Guanfacine, which is an alpha-2 agonist with a higher affinity for the 2A, compared with 2B or 2C, subtypes, also blocked the ability of PCP to increase dopamine efflux in the prefrontal cortex. These data indicate that alpha-2A agonists are effective at counteracting the hyperdopaminergic state induced by PCP and may play a role in their neurobehavioral effects in this putative animal model for schizophrenia.
doi:10.1016/j.brainres.2008.10.006
PMCID: PMC2674271  PMID: 18977208
Phencyclidine; Dopamine; Norepinephrine; Adrenoceptor; Prefrontal cortex; Microdialysis
9.  Neuropeptide S: A transmitter system in the brain regulating fear and anxiety 
Neuropharmacology  2009;58(1):29-34.
Summary
The recently discovered Neuropeptide S (NPS) and its cognate receptor represent a highly interesting system of neuromodulation with unique physiological effects. On one hand, NPS increases wakefulness and arousal. On the other, NPS produces anxiolytic-like effects by acutely reducing fear responses as well as modulating long-term aspects of fear memory, such as attenuation of contextual fear or enhancement of fear extinction. The main sources of NPS in the brain are a few clusters of NPS-producing neurons in the brainstem. NPS binds to a G-protein-coupled receptor that is highly conserved among vertebrates and stimulates mobilization of intracellular Ca2+ as well as activation of protein kinases. In synaptic circuits within the amygdala, which are important for processing of acute fear as well as formation and expression of fear memories, NPS causes increased release of the excitatory transmitter glutamate, especially in synaptic contacts to a subset of GABAergic interneurons. Polymorphisms in the human NPS receptor gene have been associated with altered sleep behavior and panic disorder. In conclusion, the NPS system displays a unique physiological profile with respect to the specificity and time course of its actions. These functions could provide interesting opportunities for both basic research and clinical applications.
doi:10.1016/j.neuropharm.2009.06.001
PMCID: PMC2784192  PMID: 19523478
Neuropeptide S; G-Protein-coupled receptor; Amygdala; Fear Behavior; Anxiety Disorder
10.  Evidence for involvement of nitric oxide and GABAB receptors in MK-801- stimulated release of glutamate in rat prefrontal cortex 
Neuropharmacology  2012;63(4):575-581.
Systemic administration of NMDA receptor antagonists elevates extracellular glutamate within prefrontal cortex. The cognitive and behavioral effects of NMDA receptor blockade have direct relevance to symptoms of schizophrenia, and recent studies demonstrate an important role for nitric oxide and GABAB receptors in mediating the effects of NMDA receptor blockade on these behaviors. We sought to extend those observations by directly measuring the effects of nitric oxide and GABAB receptor mechanisms on MK-801-induced glutamate release in the prefrontal cortex. Systemic MK-801 injection (0.3 mg/kg) to male Sprague-Dawley rats significantly increased extracellular glutamate levels in prefrontal cortex, as determined by microdialysis. This effect was blocked by pretreatment with the nitric oxide synthase inhibitor L-NAME (60 mg/kg). Reverse dialysis of the nitric oxide donor SNAP (0.5 – 5 mM) directly into prefrontal cortex mimicked the effect of systemic MK-801, dose-dependently elevating cortical extracellular glutamate. The effect of MK-801 was also blocked by systemic treatment with the GABAB receptor agonist baclofen (5 mg/kg). In combination, these data suggest increased nitric oxide formation is necessary for NMDA antagonist-induced elevations of extracellular glutamate in the prefrontal cortex. Additionally, the data suggest GABAB receptor activation can modulate the NMDA antagonist-induced increase in cortical glutamate release.
doi:10.1016/j.neuropharm.2012.04.032
PMCID: PMC3392446  PMID: 22579658
glutamate; nitric oxide; MK-801; GABA; NMDA receptor; schizophrenia
11.  Alterations in NMDA Receptor Subunit Densities and Ligand Binding to Glycine Recognition Sites are Associated with Chronic Anxiety in Alzheimer’s Disease 
Neurobiology of aging  2007;29(10):1524-1532.
Glutamatergic deficits are established neuropathological features of Alzheimer’s disease (AD) and are known to correlate with cognitive impairments. In contrast, the role of glutamatergic alterations in behavioral and psychological symptoms of dementia (BPSD) is unclear. There is considerable preclinical evidence for the importance of glycine recognition sites (GlyRS) of Nmethyl-d-aspartate (NMDA) receptors in the regulation of anxiety behaviors. This study aimed to correlate several glutamatergic measures with chronic anxiety in AD. 21 AD patients assessed by the Neuropsychiatric Inventory (NPI) were divided into low anxiety (LA) and high anxiety (HA) subgroups. GlyRS and NMDA channel were measured by brain homogenate binding with [3H]MDL105,519 and [3H]MK-801, respectively. Densities of NMDA receptor NR2A, NR2B and alternate spliced NR1 subunits were quantified by immunoblotting. We found that the binding affinity to GlyRS was significantly higher in HA compared to LA, and this higher GlyRS affinity correlated with selective reduction of NR2A density as well as with elevated anxiety scores. Our observations suggest a novel mechanism whereby subunit specific changes in the NMDA receptor complex may be linked to chronic anxiety in AD via effects on GlyRS function. We propose that NR2A and GlyRS should be further assessed as novel targets of behavioral pharmacotherapy in AD.
doi:10.1016/j.neurobiolaging.2007.03.014
PMCID: PMC2667969  PMID: 17433503
12.  Glutamatergic and GABAergic modulations of ultrasonic vocalizations during maternal separation distress in mouse pups 
Psychopharmacology  2008;204(1):61-71.
Introduction
Dysregulation of GABAergic inhibition and glutamatergic excitation has been implicated in exaggerated anxiety. Mouse pups emit distress-like ultrasonic vocalizations (USVs) when they are separated from their dam/siblings, and this behavior is reduced by benzodiazepines (BZs) which modulate GABAergic inhibition. The roles of glutamate receptors on USVs remain to be investigated.
Materials and methods
We examined the roles of glutamate receptor subtypes on mouse pup USVs using N-methyl-D-aspartate (NMDA) receptor antagonists with different affinities [dizocilpine (MK-801), memantine, and neramexane] and group II metabotropic glutamate receptor agonist (LY-379268) and antagonist (LY-341495). These effects were compared with classic BZs: flunitrazepam, bromazepam, and chlordiazepoxide. To assess the role of GABAA receptor subunits on USVs, drugs that have preferential actions at different GABAA-α subunits (L-838417 and QH-ii-066) were tested. Seven-day-old CFW mouse pups were separated from their dam and littermates and placed individually on a 19°C test platform for 4 min. Grid crossings and body rolls were measured in addition to USVs.
Results
Dizocilpine dose-dependently reduced USVs, whereas memantine and neramexane showed biphasic effects and enhanced USVs at low to moderate doses. The NMDA receptor antagonists increased locomotion. LY-379268 reduced USVs but also suppressed locomotion. All BZs reduced USVs and increased motor incoordination. Neither L-838417 nor QH-ii-066 changed USVs, but both induced motor incoordination.
Conclusion
Low-affinity NMDA receptor antagonists, but not the high-affinity antagonist, enhanced mouse pup distress calls, which may be reflective of an anxiety-like state. BZs reduced USVs but also induced motor incoordination, possibly mediated by the α5 subunit containing GABAA receptors.
doi:10.1007/s00213-008-1437-8
PMCID: PMC2758424  PMID: 19099296
Anxiety; Ultrasonicvocalizations; Mousepups; NMDA receptor; mGluR2/3; GABAA receptor subtypes; Motor activity; Motor incoordination
13.  The Role of 5-HT3 and Other Excitatory Receptors in Central Cardiorespiratory Responses to Hypoxia: Implications for Sudden Infant Death Syndrome 
Pediatric research  2009;65(6):625-630.
While brainstem serotonergic (5-HT) systems are involved in the protective responses to hypoxia, abnormalities of 5-HT function are strongly implicated in SIDS, and the neurochemical mechanisms by which 5-HT receptors influence brainstem cardiorespiratory responses to hypoxia remains unclear. This study focuses on the role of excitatory neurotransmission, including 5-HT3 signaling, to cardiac vagal neurons (CVNs) that dominate the control of heart rate. Excitatory synaptic inputs to CVNs, located in the nucleus ambiguus (NA), were recorded simultaneously with respiratory activity in in-vitro brainstem slices. During control conditions excitatory inputs to CVNs were blocked by application of NMDA and AMPA/kainate glutamatergic receptor antagonists, while the 5-HT3 and purinergic receptor antagonists ondansetron and pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), respectively, had no effect. However, during hypoxia ondansetron inhibited excitatory neurotransmission to CVNs. In recovery from hypoxia, spontaneous and respiratory-related excitatory events were blocked by glutamatergic and purinergic receptor blockers, respectively, while ondancetron had no effect. These results demonstrate that hypoxia recruits a 5-HT pathway to CVNs that activates 5-HT3 receptors on CVNs to maintain parasympathetic cardiac activity during hypoxia. Exaggeration of this 5-HT neurotransmission could increase the incidence of bradycardia and risk of sudden infant death during hypoxia.
doi:10.1203/PDR.0b013e3181a16e9c
PMCID: PMC2693719  PMID: 19247214
14.  Input-specific Plasticity of NMDA Receptor- Mediated Synaptic Responses in Neonatal Rat Motoneurons 
The European journal of neuroscience  2009;29(11):2125-2136.
Lumbar motoneurons can be activated monosynaptically by two glutamatergic synaptic inputs: segmental dorsal root (DR) and descending ventrolateral funiculus (VLF). To determine if their N-methyl-D-aspartate (NMDA) receptors are independent, we used (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-hydrogen-maleate (MK-801), known to induce a use-dependent irreversible block of NMDA receptors (NMDAR). In the presence of MK-801 (in bath) and non-NMDA antagonists (in bath, to isolate NMDA receptors pharmacologically) we first stimulated DR. After MK-801 blockade of DR synaptic input, the VLF was stimulated. Its response was found to be not significantly different than its control value suggesting that the DR stimulus activated very few if any receptors also activated by VLF stimulation. Similar findings were made if the stimulation order was reversed. Both inputs also elicited a polysynaptic NMDA receptor- mediated response. Evoking the DR polysynaptic response in the presence of MK-801 eliminated the corresponding VLF response; the reverse did not occur. Surprisingly, when MK-801 was washed from the bath, both DR and VLF responses could recover although the recovery of the DR monosynaptic and polysynaptic responses was reliably greater than those associated with VLF. Recovery was prevented if extrasynaptic receptors were activated by bath applied NMDA in the presence of MK-801 consistent with the possibility that recovery was due to movement of extrasynaptic receptors into parts of the membrane accessible to transmitter released by DR and VLF stimulation. These novel findings suggest that segmental glutamatergic inputs to motoneurons are more susceptible to plastic changes than those from CNS white matter inputs at this developmental stage.
doi:10.1111/j.1460-9568.2009.06769.x
PMCID: PMC2931593  PMID: 19490018
MK-801; EPSP; NMDA receptor mobility
15.  The Behavioral and Pharmacological Actions of NMDA Receptor Antagonism are Conserved in Zebrafish Larvae 
Dizocilpine maleate (MK-801) is one of several NMDA receptor antagonists that is widely used to pharmacologically model the symptoms of psychosis and schizophrenia in animals. MK-801 elicits behaviors in adult zebrafish (Danio rerio) that are phenotypically consistent with behaviors observed in humans and rodents exposed to tbhe drug. However, the molecular and cellular processes that mediate the psychotomimetic, cognitive and locomotive behaviors of MK-801 are unclear. We exposed zebrafish larvae to MK-801 to assess their merit as a model organism to elucidate the behavioral effects of NMDA receptor blockade. Zebrafish larvae were acutely immersed in MK-801 to assess the effect on spontaneous swimming. MK-801 caused a time- and dose-dependent increase in larval swim speed, and the peak response (a five-fold increase in swim speed) was evoked by a three h exposure to a 20 uM dose. Zebrafish larvae did not exhibit sensitivity to the locomotor effects of MK-801 until 5 dpf, suggesting a critical role for developmental in sensitivity to the drug. Exposure to the low potency NMDA antagonist, memantine, did not alter the swim speed of zebrafish larvae. Co-immersion in D1 or D2 dopamine receptor antagonists did not disrupt the time course or magnitude of the increase in swim speed, suggesting dopaminergic signaling is not required for the locomotor actions of MK-801. Our findings of the behavioral actions of MK-801 in zebrafish larvae are consistent with previous observations in mammals and imply that the physiological, cellular and molecular processes disrupted by MK-801 are conserved in zebrafish larvae. These data suggest that the zebrafish larvae is a valid and useful model to elucidate neurobehavioral aspects of NMDA receptor antagonism and may provide insight to the neurobiology of psychosis and schizophrenia.
PMCID: PMC3027073  PMID: 21278812
16.  Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex 
Neuropsychopharmacology  2012;37(6):1387-1396.
N-methyl--aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.
doi:10.1038/npp.2011.324
PMCID: PMC3327844  PMID: 22257896
NMDA receptor; phencyclidine; glutamatergic neuron; neurogenesis; neuronal progenitor; schizophrenia; animal models; biological psychiatry; glutamate; neuropharmacology; development
17.  NMDA or non-NMDA Receptor Antagonism within the Amygdaloid Central Nucleus Suppresses the Affective Dimension of Pain in Rats: Evidence for Hemispheric Synergy 
The Journal of Pain  2012;13(4):328-337.
The amygdala contributes to generation of affective behaviors to threats. The prototypical threat to an individual is exposure to a noxious stimulus and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study evaluated the contribution of glutamate receptors in CeA to generation of the affective response to acute pain in rats. Vocalizations that occur following a brief noxious tailshock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed by bilateral injection into CeA of the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (AP5, 1μg, 2μg, or 4μg) or the non-NMDA receptor antagonist 6-Cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX, .25μg, .5μg, 1μg, or 2μg). Vocalizations that occur during tailshock were suppressed to a lesser degree, whereas, spinal motor reflexes (tail flick and hindlimb movements) were unaffected by injection of AP5 or CNQX into CeA. Unilateral administration of AP5 or CNQX into CeA of either hemisphere also selectively elevated vocalization thresholds. Bilateral administration of AP5 or CNQX produced greater increases in vocalization thresholds than the same doses of antagonists administered unilaterality into either hemisphere indicating synergistic hemispheric interactions.
Perspective
The amygdala contributes to production of emotional responses to environmental threats. Blocking glutamate neurotransmission within the central nucleus of the amygdala suppressed rats’ emotional response to acute painful stimulation. Understanding the neurobiology underlying emotional responses to pain will provide insights into new treatments for pain and its associated affective disorders.
doi:10.1016/j.jpain.2011.12.007
PMCID: PMC3329962  PMID: 22424916
nociception; emotion; laterality; amygdala; AP-5; CNQX; vocalization; rat; glutamate
18.  Role of Thalamic Projection in NMDA Receptor-Induced Disruption of Cortical Slow Oscillation and Short-Term Plasticity 
NMDA receptor (NMDAR) antagonists, such as phencyclidine, ketamine, or dizocilpine (MK-801) are commonly used in psychiatric drug discovery in order to model several symptoms of schizophrenia, including psychosis and impairments in working memory. In spite of the widespread use of NMDAR antagonists in preclinical and clinical studies, our understanding of the mode of action of these drugs on brain circuits and neuronal networks is still limited. In the present study spontaneous local field potential (LFP), multi- (MUA) and single-unit activity, and evoked potential, including paired-pulse facilitation (PPF) in response to electrical stimulation of the ipsilateral subiculum were carried out in the medial prefrontal cortex (mPFC) in urethane anesthetized rats. Systemic administration of MK-801 (0.05 mg/kg, i.v.) decreased overall MUA, with a diverse effect on single-unit activity, including increased, decreased, or unchanged firing, and in line with our previous findings shifted delta-frequency power of the LFP and disrupted PPF (Kiss et al., 2011). In order to provide further insight to the mechanisms of action of NMDAR antagonists, MK-801 was administered intracranially into the mPFC and mediodorsal nucleus of the thalamus (MD). Microinjections of MK-801, but not physiological saline, localized into the MD evoked changes in both LFP parameters and PPF similar to the effects of systemically administered MK-801. Local microinjection of MK-801 into the mPFC was without effect on these parameters. Our findings indicate that the primary site of the action of systemic administration of NMDAR antagonists is unlikely to be the cortex. We presume that multiple neuronal networks, involving thalamic nuclei contribute to disrupted behavior and cognition following NMDAR blockade.
doi:10.3389/fpsyt.2011.00014
PMCID: PMC3089990  PMID: 21556284
MK-801; paired-pulse facilitation; local field potential; unit activity; medial prefrontal cortex; localized drug microinjection; subiculum; schizophrenia
19.  AN NMDA ANTAGONIST IN THE MPOA IMPAIRS COPULATION AND STIMULUS SENSITIZATION IN MALE RATS 
Behavioral Neuroscience  2012;126(1):186-195.
Systemic injections of an NMDA antagonist have been shown to impair mating in male rats. One site where glutamate and its NMDA receptors may contribute to mating is the medial preoptic area (MPOA), which is vital for male sexual behavior. Glutamate is released in the MPOA during copulation, and especially at the time of ejaculation. We report here that the NMDA antagonist MK-801, microinjected into the MPOA, impaired copulatory behavior in sexually naïve as well as experienced males. In animals tested both as naïve and after sexual experience, drug treatment produced more profound impairment in naïve males. In addition, MK-801, microinjected into the MPOA before each of 7 noncopulatory exposures to receptive female rats, resulted in copulatory impairments on a drug-free test on day 8, relative to aCSF-treated animals; their behavior was similar to that of males that had not been pre-exposed to females. Therefore, NMDA receptors in the MPOA contribute to the control of copulation and stimulus sensitization. Glutamate, acting via NMDA receptors, regulates many neural functions, including neuronal plasticity. This is the first demonstration that a similar mechanism in the MPOA sensitizes male rats to the stimuli from a receptive female, and thereby enhances their behavior.
doi:10.1037/a0026460
PMCID: PMC3270382  PMID: 22289046
Sexual behavior; Medial Preoptic Area; glutamate; NMDA; MK-801; Dizocilpine
20.  The role of glutamatergic inputs onto parvalbumin-positive interneurons: relevance for schizophrenia 
Reviews in the neurosciences  2012;23(1):97-109.
Cognitive impairment, a core feature of schizophrenia, has been suggested to arise from a disturbance of gamma oscillations that is due to decreased neurotransmission from the parvalbumin (PV) subtype of interneurons. Indeed, PV interneurons have uniquely fast membrane and synaptic properties that are crucially important for network functions such as feedforward inhibition or gamma oscillations. The causes leading to impairment of PV neurotransmission in schizophrenia are still under investigation. Interestingly, NMDA receptors (NMDARs) antagonism results in schizophrenia-like symptoms in healthy adults. Additionally, systemic NMDAR antagonist administration increases prefrontal cortex pyramidal cell firing, apparently by producing disinhibition, and repeated exposure to NMDA antagonists leads to changes in the GABAergic markers that mimic the impairments found in schizophrenia. Based on these findings, PV neuron deficits in schizophrenia have been proposed to be secondary to (NMDAR) hypofunction at glutamatergic synapses onto these cells. However, NMDARs generate long-lasting postsynaptic currents that result in prolonged depolarization of the postsynaptic cells, a property inconsistent with the role of PV cells in network dynamics. Here, we review evidence leading to the conclusion that cortical disinhibition and GABAergic impairment produced by NMDAR antagonists are unlikely to be mediated viaNMDARs at glutamatergic synapses onto mature cortical PV neurons.
doi:10.1515/revneuro-2011-0059
PMCID: PMC3607105  PMID: 22718616
cognition; GABA; NMDA; oscillations
21.  Prolonged Exposure to NMDAR Antagonist Induces Cell-type Specific Changes of Glutamatergic Receptors in Rat Prefrontal Cortex 
Neuropharmacology  2011;62(4):1808-1822.
N-methyl-D-aspartic acid (NMDA) receptors are critical for both normal brain functions and the pathogenesis of schizophrenia. We investigated the functional changes of glutamatergic receptors in the pyramidal cells and fast-spiking (FS) interneurons in the adolescent rat prefrontal cortex in MK-801 model of schizophrenia. We found that although both pyramidal cells and FS interneurons were affected by in vivo subchronic blockade of NMDA receptors, MK-801 induced distinct changes in αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors in the FS interneurons compared with pyramidal cells. Specifically, the amplitude, but not the frequency, of AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs) in FS interneurons was significantly decreased whereas both the frequency and amplitude in pyramidal neurons were increased. In addition, MK-801-induced new presynaptic NMDA receptors were detected in the glutamatergic terminals targeting pyramidal neurons but not FS interneurons. MK-801 also induced distinct alterations in FS interneurons but not in pyramidal neurons, including significantly decreased rectification index and increased calcium permeability. These data suggest a distinct cell-type specific and homeostatic synaptic scaling and redistribution of AMPA and NMDA receptors in response to the subchronic blockade of NMDA receptors and thus provide a direct mechanistic explanation for the NMDA hypofunction hypothesis that have long been proposed for the schizophrenia pathophysiology.
doi:10.1016/j.neuropharm.2011.11.024
PMCID: PMC3269523  PMID: 22182778
MK-801; AMPA receptors; fast-spiking interneurons; NMDA receptor hypofunction; schizophrenia
22.  Amygdala-prefrontal pathways and the dopamine system affect nociceptive responses in the prefrontal cortex 
BMC Neuroscience  2011;12:115.
Background
We previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC). The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA) to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS) delivered to the BLA on nociceptive responses in the rat PFC.
Results
HFS induced long lasting suppression (LLS) of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA) receptor antagonists (2-amino-5-phosphonovaleric acid (APV), dizocilpine (MK-801)) and also metabotropic glutamate receptor (mGluR) group antagonists (α-methyl-4-carboxyphenylglycine (MCPG), and 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (LY341495)), prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA) on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA) injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride) and D4 (3-{[4-(4-chlorophenyl) piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870)), microinjected into the PFC, inhibited LLS of nociceptive responses.
Conclusions
Our results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.
doi:10.1186/1471-2202-12-115
PMCID: PMC3228703  PMID: 22085449
23.  GluN1 hypomorph mice exhibit wide-ranging behavioral alterations 
Genes, Brain, and Behavior  2012;11(3):342-351.
The psychotomimetic effects of N-methyl-d-aspartate receptor (NMDA) antagonists such as ketamine and phencyclidine suggest a role for reduced NMDA receptor-mediated neurotransmission in schizophrenia. GluN1 ‘hypomorph’ (GluN1hypo) mice exhibit reduced NMDA receptor expression and have been suggested as a mouse model of schizophrenia. However, NMDA receptors are ubiquitous and are implicated in many physiological and pathological processes. The GluN1hypo mice have a global reduction of NMDA receptors and the consequences of such a global manipulation are likely to be wide-ranging. We therefore assessed GluN1hypo mice on a battery of behavioral tests, including tests of naturalistic behaviors, anxiety and cognition. GluN1hypo mice exhibited impairments on all tests of cognition that we employed, as well as reduced engagement in naturalistic behaviors, including nesting and burrowing. Behavioral deficits were present in both spatial and non-spatial domains, and included deficits on both short- and long-term memory tasks. Results from anxiety tests did not give a clear overall picture. This may be the result of confounds such as the profound hyperactivity seen in GluN1hypo mice, although hyperactivity cannot account for all of the results obtained. When viewed against this background of far-reaching behavioral abnormalities, the specificity of any one behavioral deficit is inevitably called into question. Indeed, the present data from GluN1hypo mice are indicative of a global impairment rather than any specific disease. The deficits seen go beyond what one would expect from a mouse model of schizophrenia, thus questioning their utility as a selective model of this disease.
doi:10.1111/j.1601-183X.2012.00767.x
PMCID: PMC3489048  PMID: 22300668
Anxiety; cognition; GluN1; mice; schizophrenia
24.  The role of endogenous neurotensin in psychostimulant-induced disruption of prepulse inhibition and locomotion 
Schizophrenia research  2011;136(1-3):88-95.
The neuropeptide neurotensin (NT) is closely associated with dopaminergic and glutamatergic systems in the rat brain. Central injection of NT into the nucleus accumbens (NAcc) or peripheral administration of NT receptor agonists, reduces many of the behavioral effects of psychostimulants. However, the role of endogenous NT in the behavioral effects of psychostimulants (e.g. DA agonists and NMDA receptor antagonists) remains unclear. Using a NTR antagonist, SR142948A, the current studies were designed to examine the role of endogenous NT in DA receptor agonist- and NMDA receptor antagonist-induced disruption of prepulse inhibition of the acoustic startle response (PPI), locomotor hyperactivity and brain-region specific c-fos mRNA expression. Adult male rats received a single i.p. injection of SR142948A or vehicle followed by d-amphetamine, apomorphine or dizocilpine challenge. SR142948A had no effect on baseline PPI, but dose-dependently attenuated D-amphetamine- and dizocilpine-induced PPI disruption and enhanced apomorphine-induced PPI disruption. SR142948A did not significantly affect either baseline locomotor activity or stimulant-induced hyperlocomotion. Systemic SR142948A administration prevented c-fos mRNA induction in mesolimbic terminal fields (prefrontal cortex, lateral septum, NAcc, ventral subiculum) induced by all three psychostimulants implicating the VTA as the site for NT modulation of stimulant-induced PPI disruption. Further characterization of the NT system may be valuable to find clinical useful compounds for schizophrenia and drug addiction.
doi:10.1016/j.schres.2011.10.013
PMCID: PMC3595536  PMID: 22104138
Prepulse inhibition; Locomotion; d-amphetamine; Apomorphine; Dizocilpine; c-fos; Neurotensin
25.  Ascorbic Acid Inhibits Development of Tolerance and Dependence to Opiates in Mice: Possible Glutamatergic or Dopaminergic Modulation 
In a recent study, it has been demonstrated that ascorbic acid possessed antidopaminergic activity and modulate the glutamatergic neurotransmission in mice. With this background, the present study was undertaken to study the effect of ascorbic acid on the development of tolerance and dependence to opiate and its mechanism of action. Male Swiss mice weighing 20-25 g were used in the present study. Mice were made physically dependent on opioid by the chronic administration of morphine (10 mg/kg, twice a day, for 9 days) intraperitoneally. Ascorbic acid, haloperidol (dopamine antagonist) or MK 801 (NMDA receptor antagonist) was administered daily for 9 d before challenging the animals with morphine. The development of tolerance was assessed by noting the tail-flick latency on day 1, 3, 9 and 10. On the 10th day after the measurement of tail-flick latency, animals were challenged with naloxone (2 mg/kg., i.p.) and incidence of escape jumps were recorded by placing the animals in 45 cm high plexiglass container. Ascorbic acid (400-1600 mg/kg) dose dependently inhibited development of tolerance and dependence to morphine as noted from tail-flick latency. When given along with MK 801 (0.01 mg/kg., i.p) or haloperidol (0.1 mg/kg i.p.), ascorbic acid (800 mg/kg., i.p.) potentiated the response of MK 801 or haloperidol. In conclusion, it is hypothesized that inhibition of development of tolerance and dependence to morphine by ascorbic acid appears to have two components, namely dopaminergic and glutamatergic.
doi:10.4103/0250-474X.40332
PMCID: PMC2852062  PMID: 20390081
Ascorbic acid; tolerance; dependence; dopamine; glutamate

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