Elevated hippocampal mGlut2 receptors in rats with metabolic syndrome-induced-memory impairment, possible protection by vitamin D.

BACKGROUND: Metabolic syndrome patients are commonly prone to major health problems as cardiovascular diseases, diabetes mellitus, chronic kidney disease, cancer and neuropsychological complications including dementia. OBJECTIVES: This research investigates mechanisms linking metabolic syndrome to cognitive impairment and possible impact of vitamin D supplementation. METHODS: Forty male Wistar rats were divided into 4 groups. Control, metabolic syndrome (20% fructose solution in drinking water for 12 weeks, vitamin D supplemented (500 IU/kg/day)) and metabolic syndrome supplemented with vitamin D. Animals were assessed for spatial memory, hippocampal expression of SNAP 25, VAMP and mGlut2 receptor and hippocampus histological examination. Animals with metabolic syndrome showed prolonged acquisition and retention latencies in morris water maze, decreased hippocampal expression of SNAP 25 and VAMP and increased mGlut2 expression. Histologically CA1, CA3 regions and dentate nucleus revealed increase in degenerated neurons and glia cells with decreased pyramidal cell layer thickness. Vitamin D supplementation mitigated alterations induced by metabolic syndrome. CONCLUSIONS: Metabolic syndrome decreased hippocampal synaptic proteins and altered glutamatergic transmission and increased hippocampal neuronal degeneration. Vitamin D supplementation offered neuroprotective effects.

Sedative-Hypnotic Agents That Impact Gamma-Aminobutyric Acid Receptors: Focus on Flunitrazepam, Gamma-Hydroxybutyric Acid, Phenibut, and Selank.

There are many nonopioid central nervous system depressant substances that share a gamma-aminobutyric acid (GABA) receptor-related mechanism of action. These sedatives-hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor-mediated sedative-hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma-hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA-modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues.

ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice.

The G-protein activated, inward-rectifying potassium (K(+)) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications.

Signalling routes and developmental regulation of group I metabotropic glutamate receptors in rat auditory midbrain neurons.

Group I metabotropic glutamate receptors (mGluRs) are linked to intracellular Ca(2+) signalling and play important roles related to synaptic plasticity and development. In neurons from the central nucleus of the inferior colliculus (CIC), the activation of these receptors evokes large [Ca(2+) ](i) responses. By using optical imaging of the fluorescent Ca(2+) -sensitive dye Fura-2, we have explored which [Ca(2+) ](i) routes are triggered by group I mGluR activation in young CIC neurons and whether mGluR-induced [Ca(2+) ](i) responses are regulated during postnatal development. In addition, real-time quantitative RT-PCR was used to study the developmental expression of both group I mGluR subtypes, mGluR1 and mGluR5. Application of DHPG, a specific agonist of group I mGluRs, was used on CIC slices from young rats to elicit [Ca(2+) ](i) responses. A majority of responses consisted of an initial thapsigargin-sensitive Ca(2+) peak, related to store depletion, followed by a plateau phase, sensitive to the store-operated Ca(2+) entry blocker 2-APB. During postnatal development, from P6 to P17, DHPG-induced [Ca(2+) ](i) responses changed. The largest Ca(2+) responses were reached at P6, whereas lower peak and plateau responses were found after hearing onset, at P13-P14 and P17. qRT-PCR analysis also revealed important differences in the expression of both mGluR1 and mGluR5 subtypes during development, with the highest levels of both subtypes at P7 and a developmental decrease of both transcripts. Our results suggest both intra- and extracellular routes for [Ca(2+) ](i) increases linked to group I mGluRs in CIC neurons and a regulation of group I mGluR activity and expression during auditory development.

4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators.

4-(1-Phenyl-1H-pyrazol-4-yl)quinoline (1) was identified by screening the Lundbeck compound collection, and characterized as having mGlu4 receptor positive allosteric modulator properties. Compound 1 is selective over other mGlu receptors and a panel of GPCRs, ion channels and enzymes, but has suboptimal lipophilicity and high plasma and brain non-specific binding. In view of the challenges at the hit-to-lead stage previously reported in the development of mGlu4 receptor positive allosteric modulators (PAMs), a thorough structure-mGlu4 PAM activity relationship study was conducted to interrogate the chemical tractability of this chemotype. The central pyrazole ring tolerates the addition of one or two methyl groups. The C-7 position of the quinoline ring provides a site tolerant to hydrophilic substituents, enabling the design of diverse analogs with good in vitro mGlu4 PAM potency and efficacy, as well as improved microsomal turnover in vitro, compared to 1. In spite of the excellent ligand efficiency of 1 (LE=0.43), optimization of in vitro potency for this series reached a plateau around EC(50)=200 nM.

Regulation of connexin 36 expression during development.

In the mammalian CNS, the expression of neuronal gap junction protein, connexin 36 (Cx36), increases during the first 2 weeks of postnatal development and then decreases during the following 2 weeks. Recently we showed that the developmental increase in Cx36 expression is augmented by chronic (2 weeks) activation of group II metabotropic glutamate receptors (mGluR), prevented by chronic receptor inactivation, and the receptor-dependent increase in Cx36 expression is regulated via transcriptional control of the Cx36 gene activity. We demonstrate here that acute (60 min) activation of group II mGluRs in developing cortical neuronal cultures causes transient increase in Cx36 protein expression with decrease during the following 24h. However, there is no change in Cx36 mRNA expression. In addition, the data indicate that transient increase in Cx36 expression is due to new protein synthesis. The results suggest that, during development, acute activation of group II mGluRs causes up-regulation of Cx36 via post-transcriptional mechanisms. However, if the receptor activation is sustained, transcriptional activation of the Cx36 gene occurs.

Metabotropic glutamate receptors in the thalamocortical network: strategic targets for the treatment of absence epilepsy.

Metabotropic glutamate (mGlu) receptors are positioned at synapses of the thalamocortical network that underlie the development of spike-and-wave discharges (SWDs) associated with absence epilepsy. The modulatory role of individual mGlu receptor subtypes on excitatory and inhibitory synaptic transmission in the cortico-thalamo-cortical circuitry makes subtype-selective mGlu receptor ligands potential candidates as novel antiabsence drugs. Some of these compounds are under clinical development for the treatment of numerous neurologic and psychiatric disorders, and might be soon available for clinical studies in patients with absence seizures refractory to conventional medications. Herein we review the growing evidence that links mGlu receptors to the pathophysiology of pathologic SWDs moving from the anatomic localization and function of distinct mGlu receptor subtypes in the cortico-thalamo-cortical network to in vivo studies in mouse and rat models of absence epilepsy.

Blockade of mGLUR5 receptors differentially alters amphetamine-induced enhancement of locomotor activity and of brain stimulation reward.

This study was aimed at determining the role of mGLUR5 glutamate receptors on amphetamine-induced enhancement of locomotion and of brain stimulation reward (BSR). The effect of different doses of the mGLUR5 antagonist, MPEP (0, 1, 3 and 9 mg/kg, i.p.), was assessed on reward induced by electrical stimulation of the lateral hypothalamus, and on the enhancement of reward by amphetamine (1 mg/kg, i.p.) in adult male Long Evans rats. The effect of a single dose of MPEP (0 and 9 mg/kg) on amphetamine-induced increase in locomotor activity was also assessed. Systemic injection of MPEP alone did not alter reward threshold and maximum rate of responding. Amphetamine produced a 25-30% decrease in reward threshold, an effect not altered by the highest dose of MPEP. At this dose, MPEP produced a weak inhibition of spontaneous locomotion and a significant attenuation of the enhanced locomotor activity induced by amphetamine. These findings show that mGLUR5 glutamate receptors are unlikely to constitute important elements of the reward-relevant pathway, and do not intervene in the enhancement effect of amphetamine. They also show, however, that these glutamate receptors play a key role in amphetamine-induced increased locomotor activity, providing additional evidence for a dissociation between the substrates that mediate these two behaviours.

N-antipyrine-3, 4-dichloromaleimide, an effective cyclic imide for the treatment of chronic pain: the role of the glutamatergic system.

BACKGROUND: In recent years, cyclic imides have attracted the attention of the scientific community because of their promising therapeutic potential. Studies with the compound N-antipyrine-3,4-dichloromaleimide (NA-3,4-DCM) also demonstrated an antinociceptive effect in formalin or capsaicin models of nociception, and that it reduced acetic acid-induced abdominal writhing in mice. METHODS: In this study, we examined the effects of NA-3,4-DCM on mechanical hypernociception in persistent pain-like behavioral models in mice. We also investigated the peripheral, topical, spinal, and supraspinal antinociceptive properties of NA-3,4-DCM and evaluated the involvement of the glutamatergic system on the antinociceptive effects of NA-3,4-DCM in mice. RESULTS: NA-3,4-DCM, dosed systemically (intraperitoneally or per os), was capable of interfering with the development of mechanical hypernociception induced by intraplantar injection of carrageenan and complete Freund adjuvant in mice. Interestingly, repeated intraperitoneal or per os treatment with NA-3,4-DCM, administered after the induction of hypernociception, also reversed the mechanical sensitization induced by complete Freund adjuvant injection or partial ligation of the sciatic nerve in mice, with lower doses than gabapentin, a drug used clinically to treat chronic pain. When administered systemically, locally, spinally, or supraspinally, NA-3,4-DCM was able to inhibit the overt nociception of both phases of the formalin test. The systemic administration of NA-3,4-DCM also reduced the nociception induced by intraplantar or intrathecal injection of glutamate in mice. Furthermore, NA-3,4-DCM caused marked inhibition of the nociceptive response induced by intrathecal injection of a group I metabotropic glutamate receptors agonist (1S,3R)-aminocyclopentane-trans-1,3-dicardboxylic acid (ACPD) or N-methyl-d-aspartate (NMDA), without interfering with nociception induced by other non-NMDA receptor agonists (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid and kainate) or by substance P. Notably, in the same range of doses, the antinociception caused by the compound NA-3,4-DCM was not associated with nonspecific effects such as changes in locomotor activity or motor coordination. CONCLUSION: These results provide strong evidence that NA-3,4-DCM produces antihypernociception in mice at peripheral, spinal, and supraspinal sites, and that interaction with the group I metabotropic glutamate receptors and NMDA receptors contributes to the mechanisms underlying its effect.

mGluR4 positive allosteric modulators with potential for the treatment of Parkinson's disease: WO09010455.

Stimulation of the metabotropic glutamate receptor 4 (mGluR4) represents a promising new approach to the symptomatic treatment of the neurodegenerative disorder Parkinson's disease (PD). Preclinical models using both agonists and positive allosteric modulators of mGluR4 have demonstrated the potential for this receptor for the treatment of PD. The present article evaluates a recent patent filed by Addex Pharma S.A. claiming a novel series of mGluR4 positive allosteric modulators. Many of the examples disclosed are active at EC(50)'s < 500 nM.

ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities.

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.

Metabotropic glutamate receptors regulate differentiation of embryonic stem cells into GABAergic neurons.

Mouse embryonic stem (ES) cells were stimulated to differentiate either as adherent monolayer cultures in DMEM/F12 supplemented with N2/B27, or as floating embryoid bodies (EBs) exposed to 1 microM retinoic acid (RA) for 4 days, starting from 4 DIV, and subsequently re-plated in DMEM/F12 medium. Adherent monolayer cultures of ES cells expressed mGlu5 receptors throughout the entire differentiation period. Selective pharmacological blockade of mGlu5 receptors with methyl-6-(phenylethynyl)-pyridine (MPEP) (1 microM, added once a day) accelerated the appearance of the neuronal marker, beta-tubulin. In addition, treatment with MPEP increased the number of cells expressing glutamate decarboxylase-65/67 (GAD(65/67)), a marker of GABAergic neurons. In floating EBs, mGlu5 receptors are progressively replaced by mGlu4 receptors. The orthosteric mGlu4/6/7/8 receptor agonist, L-2-amino-4-phosphonobutanoate (L-AP4), or the selective mGlu4 receptor enhancer, PHCCC,--both combined with RA at concentrations of 30 microM--increased the expression of both beta-tubulin and GAD(65/67), inducing the appearance of fully differentiated neurons that released GABA in response to membrane depolarization. We conclude that mGlu receptor subtypes regulate neuronal differentiation of ES cells in a context-dependent manner, and that subtype-selective ligands of these receptors might be used for the optimization of in vitro protocols aimed at producing GABAergic neurons from ES cells.

Hyperammonaemia alters the mechanisms by which metabotropic glutamate receptors in nucleus accumbens modulate motor function.

Activation of metabotropic glutamate receptors by injecting (S)3,5-dihydroxyphenylglycine (DHPG) in nucleus accumbens (NAcc) increases motor activity by different mechanisms in control rats and in rats with chronic liver failure due to portacaval shunt. In control rats DHPG increases extracellular dopamine in NAcc and induces locomotion by activating the 'normal' circuit: NAcc-->ventral pallidum-->medial-dorsal thalamus-->prefrontal cortex, which is not activated in portacaval shunt rats. In these rats, DHPG activates an 'alternative' circuit: NAcc-->substantia nigra pars reticulata-->ventro-medial thalamus-->prefrontal cortex, which is not activated in control rats. The reasons by which liver failure leads to activation of this 'alternative' circuit remain unclear. The aim of this work was to assess whether hyperammonaemia could be responsible for the alterations found in chronic liver failure. We injected DHPG in NAcc of control or hyperammonaemic rats and analysed, by in vivo brain microdialysis, the neurochemical responses of the 'normal' and 'alternative' circuits. In hyperammonaemic rats DHPG injection in NAcc activates both the 'normal' and 'alternative' circuits. In hyperammonaemia, activation of the 'alternative' circuit and increased motor response following metabotropic glutamate receptors activation in NAcc seem due to an increase in extracellular glutamate which activates AMPA receptors.

Are compounds acting at metabotropic glutamate receptors the answer to treating depression?

Numerous studies over the last few years have suggested that modulating the glutamatergic system may be an efficient method to achieve an antidepressant effect. Data suggest that metabotropic glutamate receptors (mGlu receptors), related to long-term, modulatory effects on glutamatergic neurotransmission, may be a good target for the development of new, effective and safe therapeutic drugs to treat several CNS disorders including depression and anxiety. Several potent, selective and systemically active orthosteric and allosteric ligands of specific mGlu receptor subtypes have been discovered and these have been tested as potential antidepressants in models of depression in rodents. The mGluR5 antagonists and group II mGlu receptor antagonists seem to be the most promising compounds with potential antidepressant-like activity; however, the efficacy of mGlu receptor ligands in the clinical setting is still an unanswered question.

Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors.

Metabotropic glutamate receptors (mGluRs) have been proposed as novel targets for the treatment of a variety of disorders. Recently, highly selective allosteric modulators of the mGluRs have been developed by several groups. These allosteric compounds provide an unprecedented degree of selectivity for individual mGluRs, allowing for more detailed functional studies on the roles of these receptors. Furthermore, the allosteric approach avoids many of the hurdles associated with the development of direct agonists as drugs, and provides a clear path forward for clinical proof-of-concept studies. Currently, both positive allosteric modulators of mGluR2 and negative allosteric modulators of mGluR5 hold promise as novel anxiolytics, and positive allosteric modulators of mGluR4 appear to be an exciting new target for the treatment of Parkinson's disease.

The anxiolytic-like activity of AIDA (1-aminoindan-1,5-dicarboxylic acid), an mGLu 1 receptor antagonist.

In the present study we examined the effects of 1-aminoindan-1,5-dicarboxylic acid (AIDA), regarded as a selective and competitive mGluR1 antagonist, in animal models of anxiety. Diazepam (1-10 mg/kg) was used as a reference drug. After intraperitoneal administration, AIDA (0.5-2 mg/kg) produced anxiolytic-like effects in the conflict drinking test and the elevated plus-maze test in rats; however, in doses up to 8 mg/kg, it was inactive in the four-plate test in mice. AIDA tested at the effective doses in the conflict drinking test changed neither the treshold current nor water intake in rats compared to vehicle treatment. AIDA (in a dose of 4 mg/kg, but not lower) increased the exploratory locomotor activity of rats measured in the open-field test, but it did not disturb rat motor coordination in the rota-rod test. The above results indicate that selective mGluR1 antagonist AIDA induces antianxiety-like effects at a low risk of acute side effects characteristic of benzodiazepines. Further studies are required to identify the sites and the mechanism of action of AIDA.

A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex.

Activation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors by hallucinogenic drugs is thought to mediate many psychotomimetic effects including changes in affect, cognition and perception. Conversely, blockade of 5-HT(2A) receptors may mediate therapeutic effects of many atypical antidepressant and antipsychotic drugs. The purpose of the present study was to determine the source of subcortical glutamatergic afferents, which would project widely throughout the anterior-posterior axis of the rat brain to the apical dendrites of layer V pyramidal cells of the medial prefrontal cortex, from which serotonin induces transmitter release via activation of 5-HT(2A) receptors. Fiber-sparing chemical lesions of the medial thalamus selectively decreased the frequency of serotonin-induced excitatory postsynaptic currents recorded from layer V pyramidal cells in the prelimbic region of the medial prefrontal cortex by 60%. In contrast, large bilateral lesions of the amygdala did not alter the serotonin response. These thalamic lesions significantly decreased the amount of binding to either mu-opioid or metabotropic glutamate 2/3 receptors in the prelimbic region of the medial prefrontal cortex as expected from previous evidence that these agonists for these receptors suppress serotonin-induced excitatory postsynaptic currents by a presynaptic mechanism. Surprisingly, the amount of specific binding to cortical 5-HT(2A) receptors was significantly increased by the medial thalamic lesions. Thus, these experiments demonstrate that activation of cortical 5-HT(2A) receptors modulates transmitter release from thalamocortical terminals. Unexpectedly, lesioning the thalamocortical terminals also alters 5-HT(2A) receptor binding in the prefrontal cortex. These findings are of interest with respect to understanding therapeutic effects of antidepressant/antipsychotic drugs and the known behavioral effects of thalamic lesions in humans.

Development of a functional reporter gene HTS assay for the identification of mGluR7 modulators.

For the identification of modulators of the metabotropic glutamate receptor mGluR7, a functional cell-based high throughput screening (HTS) assay was developed. This assay utilizes the signal transduction pathway of mGluR7, which is negatively coupled to adenylyl cyclase. A cAMP-responsive luciferase reporter gene and rat mGluR7 cDNA were cotransfected into CHO-K1 cells by electroporation. Stable recombinant cells were selected by resistance to the antibiotic G418. Functional selection was carried out by analyzing the effect of the agonist glutamate to reduce elevated cAMP levels after forskolin stimulation. Out of 83 G418-resistant cell clones, the clone with the best functional characteristics was selected. This clone displayed the strongest reduction of forskolin-stimulated cAMP levels. Glutamate (10 mM) decreased cAMP levels, as monitored by luciferase expression, by about 50%, and the more potent agonist L-2-amino-4-phosphonobutyrate resulted in nearly complete reduction, exhibiting an EC(50) of 0.9 mM. The functional response of the clone did not change during cell passages, indicating the stability of this novel recombinant cell line. The luciferase reporter gene assay, which allows easy nonradioactive luminescence detection of mGluR7 activity, was optimized for its application in automated HTS.

Modulation of absence seizures by the GABA(A) receptor: a critical rolefor metabotropic glutamate receptor 4 (mGluR4).

Experimental absence seizures are associated with perturbations in the presynaptic release of GABA and glutamate within thalamocortical circuitry. The release of both glutamate and GABA is regulated by group III metabotropic glutamate receptors (mGluRs). Therefore, we examined the susceptibility of mice lacking the mGluR4 subtype of mGluR (mGluR4(-/-)) versus their wild-type controls (mGluR4(+/+)) to absence seizures induced either by gamma-hydroxybutyrate (GHB) or the GABA(B) agonist (-) baclofen or by low doses of the GABA(A) receptor (GABA(A)R) antagonists pentylenetetrazole, bicuculline, or picrotoxin. There was no difference between mGluR4(-/-) and mGluR4(+/+) mice in threshold to absence seizures induced by either GHB or (-) baclofen. In contrast, the mGluR4(-/-) mice were markedly resistant to absence seizures induced by low doses of GABA(A)R antagonists. No differences were observed between mGluR4(-/-) and mGluR4(+/+) mice in threshold to clonic or tonic seizures induced by higher doses of GABA(A)R antagonists, strychnine, or electroshock, indicating that seizure resistance in the mGluR4(-/-) mice was restricted solely to absence seizures. The resistance of mGluR4(-/-) mice to absence seizures induced by GABA(A)R antagonists was mimicked by bilateral administration of a mGluR4 antagonist into the nucleus reticularis thalami (nRT) of mGluR4(+/+) mice. Conversely, intra-nRT administration of a mGluR4 agonist in mGluR4(+/+) mice exacerbated GABA(A)R-induced absence seizures. These data indicate that the presence of mGluR4 within nRT is critical to GABAergic modulation of thalamocortical synchronization in normal and pathological states, such as generalized absence epilepsy.