6-cyano-7-nitroquinoxaline-2-3-dione and 3-4-dihydroxyphenylglycol

We examined effects of Group I metabotropic glutamate receptors on the excitability of mouse medial nucleus of the trapezoid body (MNTB) neurons. The selective agonist, S-3,5-dihydroxyphenylglycine (DHPG), evoked a dose-dependent depolarization of the resting potential, increased membrane resistance, increased sag depolarization, and promoted rebound action potential firing. Under voltage-clamp, DHPG evoked an inward current, referred to as I

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Amiloride; Animals; Dizocilpine Maleate; Excitatory Amino Acid Agents; Female; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Neurons; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Pyrimidines; Receptors, Metabotropic Glutamate; Sodium Channel Blockers; Synaptic Potentials; Tetrodotoxin; Trapezoid Body

The translation of dendritic microtubule-associated protein 1B (MAP1B) is exaggerated upon group I mGluR activation leading to AMPA receptor (AMPAR) endocytosis and consequent long-term depression. However, the mechanisms of regulation of MAP1B protein synthesis in the mature dendrites remain unclear. Here we have identified miR-146a-5p that targets the 3' UTR of MAP1B mRNA and represses its translation. Inhibition of the endogenous miR-146a-5p in mouse cultured hippocampal neurons triggers an increase of the dendritic MAP1B protein as well as the internalization of AMPARs, resulting in a decline in synaptic transmission. Conversely, enforced expression of miR-146a-5p inhibits MAP1B translation and attenuates group I mGluR-induced AMPAR endocytosis. Moreover, siRNA-mediated knockdown of MAP1B recovers the impairment of synaptic transmission caused by inhibition of miR-146a-5p. These results reveal that miR-146a-5p modulates the synaptic plasticity via repression of MAP1B protein synthesis.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Cells, Cultured; Dendrites; Electric Stimulation; Embryo, Mammalian; Endocytosis; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Female; Gene Expression Regulation; Hippocampus; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; MicroRNAs; Microtubule-Associated Proteins; Neurons; Patch-Clamp Techniques; Receptors, AMPA; RNA, Messenger; RNA, Small Interfering; Transfection; Valine

Metabotropic glutamate (mGlu) receptors modulate pain from within the midbrain periaqueductal grey (PAG). In the present study, the postsynaptic mGlu receptor mediated effects on rat PAG neurons were examined using whole-cell patch-clamp recordings in brain slices. The selective group I agonist DHPG (10 μM) produced an inward current in all PAG neurons tested which was associated with a near parallel shift in the current-voltage relationship. By contrast, the group II and III mGlu receptor agonists DCG-IV (1 μM) and l-AP4 (3 μM) produced an outward current in only 10-20% of PAG neurons tested. The DHPG induced current was concentration dependent (EC(50) = 1.4 μM), was reduced by the mGlu1 antagonist CPCCOEt (100 μM), and was further reduced by CPCCOEt in combination with the mGlu5 antagonist MPEP (10 μM). The glutamate transport blocker TBOA (30 μM) also produced an inward current, however, this was largely abolished by CNQX (10 μM) plus AP5 (25 μM). Slow EPSCs were evoked following train, but not single shock stimulation, which were enhanced by TBOA (30 μM). The TBOA enhancement of slow EPSCs was abolished by MPEP plus CPCCOEt. These findings indicate that endogenously released glutamate, under conditions in which neurotransmitter spill-over is enhanced, activates group I mGlu receptors to produce excitatory currents within PAG. Thus, postsynaptic group I mGlu receptors have the potential to directly modulate the analgesic, behavioural and autonomic functions of the PAG. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Aminobutyrates; Animals; Aspartic Acid; Chromones; Cyclopropanes; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Female; Glycine; Male; Membrane Potentials; Methoxyhydroxyphenylglycol; Neurons; Periaqueductal Gray; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate

Plastic changes in cortical activities induced by group I metabotropic glutamate receptor (mGluR) stimulation include epileptogenesis, expressed in vitro as the conversion of normal neuronal activity to persistent, prolonged synchronized (ictal) discharges. At present, the mechanism that maintains group I mGluR-induced plasticity is not known. We examined this issue using hippocampal slices from guinea pigs and mice. Agonist [(S)-3,5-dihydroxyphenylglycine (DHPG), 30-50 μm)] stimulation of group I mGluRs induces persistent prolonged synchronized (ictal-like) discharges in CA3 that are associated with three identified excitatory cellular responses-suppression of spike afterhyperpolarizations, activation of a voltage-dependent cationic current, and increase in neuronal input resistance. Persistent prolonged synchronized discharges and the underlying excitatory cellular responses maintained following induction were reversibly blocked by mGluR1 antagonists [(S)-+-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY 367385), 50, 100 μm; CPCCOEt (hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, 100 μm], and to a lesser extent by the mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride, 50 μm]. Activation of persistent cellular responses to DHPG were unaffected by tetrodotoxin (0.5-1 μm) or perfusion with low Ca(2+)(0.2 mm)-Mn(2+)(0.5 mm) media-conditions that suppress endogenous glutamate release. The pharmacological profile of the blocking action of the group I mGluR antagonist MCPG [(RS)-α-methyl-4-carboxyphenylglycine, 50-500 μm] on persistent cellular responses was different from that on cellular responses directly activated by DHPG. These data indicate that transient stimulation of group I mGluRs alters receptor properties, rendering them persistently active in the absence of applied agonist or endogenous glutamate activation. Persistent receptor activities, primarily involving mGluR1, maintain excitatory cellular responses and emergent prolonged synchronized discharges.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; CA3 Region, Hippocampal; Guinea Pigs; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Knockout; Neuronal Plasticity; Neurons; Organ Culture Techniques; Receptors, Metabotropic Glutamate

In the mammalian central nervous system, slow synaptic excitation involves the activation of metabotropic glutamate receptors (mGluRs). It has been proposed that C1-type transient receptor potential (TRPC1) channels underlie this synaptic excitation, but our analysis of TRPC1-deficient mice does not support this hypothesis. Here, we show unambiguously that it is TRPC3 that is needed for mGluR-dependent synaptic signaling in mouse cerebellar Purkinje cells. TRPC3 is the most abundantly expressed TRPC subunit in Purkinje cells. In mutant mice lacking TRPC3, both slow synaptic potentials and mGluR-mediated inward currents are completely absent, while the synaptically mediated Ca2+ release signals from intracellular stores are unchanged. Importantly, TRPC3 knockout mice exhibit an impaired walking behavior. Taken together, our results establish TRPC3 as a new type of postsynaptic channel that mediates mGluR-dependent synaptic transmission in cerebellar Purkinje cells and is crucial for motor coordination.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Behavior, Animal; Calcium; Cerebellum; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; In Vitro Techniques; Methoxyhydroxyphenylglycol; Mice; Mice, Knockout; Nerve Tissue Proteins; Neural Pathways; Patch-Clamp Techniques; Psychomotor Performance; Purkinje Cells; Synaptic Transmission; TRPC Cation Channels

Metabotropic glutamate receptor 5 (mGluR5) plays a critical role in psychostimulant-induced behavior, yet it is unclear whether mGluR5 is activated by psychostimulant administration, or whether its role is constitutive. We previously reported that activation of mGluR5 with the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) can induce a long-term depression (DHPG-LTD) of glutamatergic transmission in the bed nucleus of the stria terminalis (BNST), and that ex vivo induction of this LTD is disrupted by repeated in vivo administration of cocaine. Here we demonstrate that DHPG-LTD is not maintained by alterations in glutamate release, and that postsynaptic endocytosis is necessary. Furthermore, we find that a single administration of cocaine produces a transient disruption of DHPG-LTD, and the duration of this disruption was increased by repeated days of cocaine administration. The disruption produced by cocaine was not permanent, because DHPG-LTD could be induced 10 d after cocaine administration. To test the role of mGluR5 in vivo in the cocaine-induced disruption of DHPG-LTD, we injected mice with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine before cocaine. mGluR5 antagonism during in vivo cocaine administration rescued subsequent ex vivo induction of DHPG-LTD. The effects of in vivo cocaine could be mimicked by application of cocaine to BNST-containing slices, suggesting that the actions of cocaine are local. Thus, using a novel strategy of in vivo antagonist-induced rescue of ex vivo agonist effects for the same receptor, we provide evidence suggesting that mGluR5 activation is actively recruited by in vivo cocaine.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Brain; Cocaine; Dopamine Uptake Inhibitors; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Long-Term Synaptic Depression; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Neurons; Patch-Clamp Techniques; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Septal Nuclei

Activation of group I metabotropic glutamate receptors (mGluRs) leads to a concerted modulation of spike afterpotentials in guinea pig hippocampal neurons including a suppression of both medium and slow afterhyperpolarizations (AHPs). Suppression of AHPs may be long-lasting, in that it persists after washout of the agonist. Here, we show that persistent AHP suppression differs from short-term, transient suppression in that distinct and additional signaling processes are required to render the suppression persistent. Persistent AHP suppression followed DHPG application for 30 min, but not DHPG application for 5 min. Persistent AHP suppression was temperature dependent, occurring at 30-31 degrees C, but not at 25-26 degrees C. Preincubation of slices in inhibitors of protein synthesis (cycloheximide or anisomycin) prevented the persistent suppression of AHPs by DHPG. Similarly, preincubation of slices in an inhibitor of p38 MAP kinase (SB 203580) prevented persistent AHP suppression. In contrast, a blocker of p42/44 MAP kinase activation (PD 98059) had no effect on persistent AHP suppression. Additionally, we show that the mGluR5 antagonist MPEP, but not the mGluR1 antagonist LY 367385, prevented DHPG-induced persistent AHP suppression. Thus persistent AHP suppression by DHPG in hippocampal neurons requires activation of mGluR5. In addition, activation of p38 MAP kinase signaling and protein synthesis are required to impart persistence to the DHPG-activated AHP suppression.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cycloheximide; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Guinea Pigs; Hippocampus; In Vitro Techniques; Membrane Potentials; Methoxyhydroxyphenylglycol; Neural Inhibition; Neurons; Protein Synthesis Inhibitors; Receptors, AMPA; Signal Transduction; Temperature

Granule and periglomerular cells in the main olfactory bulb express group I metabotropic glutamate receptors (mGluRs). The group I mGluR agonist 3,4-dihydroxyphenylglycine (DHPG) increases GABAergic spontaneous IPSCs (sIPSCs) in mitral cells, yet the presynaptic mechanism(s) involved and source(s) of the IPSCs are unknown. We investigated the actions of DHPG on sIPSCs and TTX-insensitive miniature IPSCs (mIPSCs) recorded in mitral and external tufted cells in rat olfactory bulb slices. DHPG, acting at mGluR1 and mGluR5, increased the rate but not amplitude of sIPSCs and mIPSCs in both cell types. The increase in mIPSCs depended on voltage-gated Ca2+ channels but persisted when ionotropic glutamate receptors and sodium spikes were blocked. Focal DHPG puffs onto granule cells or bath application after glomerular layer (GL) excision failed to increase mIPSCs in mitral cells. Additionally, GL excision reduced sIPSCs in mitral cells by 50%, suggesting that periglomerular cells exert strong tonic GABAergic inhibition of mitral cells. In contrast, GL DHPG puffs readily increased mIPSCs. These findings indicate that DHPG-evoked GABA release from granule cells requires spikes, whereas in the GL, DHPG facilitates periglomerular cell GABA release via both spike-dependent and spike-independent presynaptic mechanisms. We speculate that mGluRs amplify spike-driven lateral inhibition through the mitral-to-granule cell circuit, whereas GL mGluRs may play a more important role in amplifying intraglomerular inhibition after subthreshold input.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dose-Response Relationship, Drug; Female; Inhibitory Postsynaptic Potentials; Male; Methoxyhydroxyphenylglycol; Neural Inhibition; Olfactory Bulb; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Synapses

While group II metabotropic glutamate receptors (mGluRs) are known to be expressed in the rat globus pallidus (GP), their functions remain poorly understood. We used standard patch clamping technique in GP slices to determine the effect of group II mGluR activation on excitatory transmission in this region. Activation of group II mGluRs with the group-selective agonist DCG-IV or APDC reduced the amplitude of the evoked excitatory postsynaptic currents (EPSCs) and significantly increased the paired pulse ratio suggesting a presynaptic site of action. This was further supported by double-labeling electron microscopy data showing that group II mGluRs (mGluR2 and 3) immunoreactivity is localized in glutamatergic pre-terminal axons and terminals in the GP. Furthermore, we found that LY 487379, an mGluR2-specific allosteric modulator, significantly potentiated the inhibitory effect of DCG-IV on the excitatory transmission in the GP. Co-incubation with 30 microM LY 487379 increased the potency of DCG-IV about 10-fold in the GP. We were thus able to pharmacologically isolate the mGluR2-mediated function in the rat GP using an mGluR2-specific allosteric modulator. Therefore, our findings do not only shed light on the functions of group II mGluRs in the GP, they also illustrate the therapeutic potential of mGluR-targeting allosteric modulators in neurological disorders such as Parkinson's disease.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acids; Aminobutyrates; Anesthetics, Local; Animals; Animals, Newborn; Cyclopropanes; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Globus Pallidus; Glycine; In Vitro Techniques; Lidocaine; Membrane Potentials; Methoxyhydroxyphenylglycol; Neurons; Patch-Clamp Techniques; Proline; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Sulfonamides; Synaptic Transmission; Xanthenes

Casein kinase 1 (CK1) is a highly conserved serine/threonine kinase, present in virtually all cell types, in which it phosphorylates a wide variety of substrates. So far, no role has been found for this ubiquitous protein kinase in the physiology of nerve cells. In the present study, we show that CK1 regulates fast synaptic transmission mediated by glutamate, the major excitatory neurotransmitter in the brain. Through the use of CK1 inhibitors, we present evidence that activation of CK1 decreases NMDA receptor activity in the striatum via a mechanism that involves activation by this kinase of protein phosphatase 1 and/or 2A and resultant increased dephosphorylation of NMDA receptors. Indeed, inhibition of CK1 increases NMDA-mediated EPSCs in medium spiny striatal neurons. This effect is associated with an increased phosphorylation of the NR1 and NR2B subunits of the NMDA receptor and is occluded by the phosphatase inhibitor okadaic acid. The mGluR1, but not mGluR5, subclass of metabotropic glutamate receptors uses CK1 to inhibit NMDA-mediated synaptic currents. These results provide the first evidence for a role of CK1 in the regulation of synaptic transmission in the brain.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Bicuculline; Casein Kinase 1 epsilon; Casein Kinase I; Casein Kinase Ialpha; Casein Kinase Idelta; Corpus Striatum; Egtazic Acid; Evoked Potentials; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glutamic Acid; Kainic Acid; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; N-Methylaspartate; Neocortex; Nerve Tissue Proteins; Okadaic Acid; Phosphoprotein Phosphatases; Protein Phosphatase 1; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Tetrodotoxin

Changes in the morphology of dendritic spines are correlated with synaptic plasticity and may relate mechanistically to its expression and stabilization. Recent work has shown that spine length can be altered by manipulations that affect intracellular calcium, and spine length is abnormal in genetic conditions affecting protein synthesis in neurons. We have investigated how ligands of group 1 metabotropic glutamate receptors (mGluRs) affect spine shape; stimulation of these receptors leads both to calcium release from intracellular stores and to dendritic protein synthesis. Thirty-minute incubation of cultured hippocampal slices and dissociated neurons with the selective group 1 mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induced a significant increase in the average length of dendritic spines. This elongation resulted mainly from the growth of existing spines and was also seen even in the presence of antagonists of ionotropic receptors, indicating that activation of these receptors by mGluR-induced glutamate release was not required. Prolonged antagonism of group 1 mGluRs with (S)-alpha-methyl-4-carboxyphenylglycine (MCPG) did not result in shorter average spine length. Elongation of dendritic spines induced by DHPG was blocked by calcium chelation and by preincubation with the protein synthesis inhibitor puromycin. The results suggest that in vivo activation of group 1 mGluRs by synaptically released glutamate affects spine shape in a protein synthesis-dependent manner.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Biolistics; Cells, Cultured; Chelating Agents; Dendrites; Egtazic Acid; Genes, Reporter; Hippocampus; Methoxyhydroxyphenylglycol; Neurons; Organ Culture Techniques; Receptors, Metabotropic Glutamate; Transfection

The cytosolic release of L-glutamate has been held to be responsible for the increase in extracellular glutamate to toxic levels in the brain. The mechanism and regulation of this release was now studied in cerebral cortical and striatal slices with D-[3H]aspartate, a non-metabolized analogue of L-glutamate and a poor substrate for vesicular uptake. L-Glutamate and D-aspartate strongly stimulated the release in a concentration-dependent manner. Of the ionotropic glutamate receptor agonists, only kainate enhanced the basal release in the striatum. Of the metabotropic glutamate receptor ligands, the group I agonist (S)-3,5-dihydroxyphenylglycine (S-DHPG) failed to affect the basal release but inhibited the D-aspartate-evoked release in the striatum. The group I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) had no effect on the basal release in either preparation but enhanced the L-glutamate-evoked release and inhibited the D-aspartate-evoked release in the striatum, not however in the cerebral cortex. The group II agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) and the group II antagonist (2S)-2-ethylglutamate (EGLU) were without effect on the basal, D-aspartate- and L-glutamate-evoked releases of D-[3H]aspartate in either preparation. The group III agonist L-serine-O-phosphate (L-SOP) failed to affect the basal release but reduced the D-aspartate-evoked release in the striatum. The group III antagonist (RS)alpha-methylserine-O-phosphate (MSOP) failed to affect the basal release but increased the glutamate-evoked release and inhibited the D-aspartate-evoked release in the striatum. Both L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC) and (2S,1'S,2'R)-2-carboxycyclopropyl)glycine (L-CCG-III), transportable inhibitors of the high-affinity glutamate uptake, enhanced the basal release, more strongly in the striatum than in the cerebral cortex. L-CCG-III also increased the L-glutamate-evoked release in the striatum. Nontransportable dihydrokainate enhanced the basal release much less and failed to affect the glutamate-evoked release. The results indicate that the release of glutamate from cytosolic pools is carrier-mediated via homoexchange. This process is regulated in the striatum by metabotropic group I and group III receptors in a manner different from the regulation of the vesicular release of glutamate from presynaptic terminals.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Aspartic Acid; Cerebral Cortex; Corpus Striatum; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; In Vitro Techniques; Kainic Acid; Kinetics; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred Strains; N-Methylaspartate; Receptors, Metabotropic Glutamate; Tritium

Postsynaptic metabotropic glutamate (mGlu) receptor-activated inward current mediated by Na(+)-Ca(2+) exchange was compared in basolateral amygdala (BLA) neurons from brain slices of control (naïve and sham-operated) and amygdala-kindled rats. In control neurons, the mGlu agonist, quisqualate (QUIS; 1-100 microM), evoked an inward current not associated with a significant change in membrane slope conductance, measured from current-voltage relationships between -110 and -60 mV, consistent with activation of the Na(+)-Ca(2+) exchanger. Application of the group I selective mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine [(S)-DHPG; 10-1000 microM] or the endogenous agonist, glutamate (10-1000 microM), elicited the exchange current. QUIS was more potent than either (S)-DHPG or glutamate (apparent EC(50) = 19 microM, 57 microM, and 0.6 mM, respectively) in activating the Na(+)-Ca(2+) exchange current. The selective mGlu5 agonist, (R, S)-2-chloro-5-hydroxyphenylglycine [(R,S)-CHPG; apparent EC(50) = 2. 6 mM] also induced the exchange current. The maximum response to (R, S)-DHPG was about half of that of the other agonists suggesting partial agonist action. Concentration-response relationships of agonist-evoked inward currents were compared in control neurons and in neurons from kindled animals. The maximum value for the concentration-response relationship of the partial agonist (S)-DHPG- (but not the full agonist- [QUIS or (R,S)-CHPG]) induced inward current was shifted upward suggesting enhanced efficacy of this agonist in kindled neurons. Altogether, these data are consistent with a kindling-induced up-regulation of a group I mGlu-, possibly mGlu5-, mediated responses coupled to Na(+)-Ca(2+) exchange in BLA neurons.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Amygdala; Animals; Calcium; Dose-Response Relationship, Drug; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Kindling, Neurologic; Male; Membrane Potentials; Methoxyhydroxyphenylglycol; Phenylacetates; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Seizures; Sodium; Tetrodotoxin; Up-Regulation

All three types of ionotropic glutamate receptors, AMPA, NMDA and kainate, contribute to the neurotransmission between inner hair cells (IHC) and afferent neurons in the mammalian cochlea. We used microiontophoretic techniques to investigate whether metabotropic glutamate receptors group I (mGluR I) are also involved in the transmission of IHC afferents of the guinea pig. The mGluR I agonist DHPG produced an increase in afferent firing, which lasted significantly longer than that of the ionotropic agonists AMPA and NMDA. The activation was reversibly blocked by the mGluR I antagonist AIDA in a dose-dependent manner. AIDA also diminished spontaneous activity, but only slightly affected the AMPA- or NMDA-induced firing rate. Our results suggest that mGluR I are involved in peripheral auditory processing.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Guinea Pigs; Hair Cells, Auditory, Inner; Indans; Methoxyhydroxyphenylglycol; N-Methylaspartate; Receptors, Metabotropic Glutamate; Synaptic Transmission