2-chloro-5-hydroxyphenylglycine and alpha-methyl-4-carboxyphenylglycine

Several subtypes of interneurons in the feedback circuit in stratum oriens of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) at glutamatergic synapses made by local pyramidal neurons. LTP has been reported with both "Hebbian" and "anti-Hebbian" induction protocols, where high-frequency presynaptic stimulation is paired with either postsynaptic depolarization or hyperpolarization. Do these phenomena represent distinct forms of plasticity, dependent on group I metabotropic receptors (mGluRs) and rectifying Ca2+ -permeable AMPA receptors, respectively? Blockade of either mGluR1 or mGluR5 prevented anti-Hebbian LTP induction in stratum oriens interneurons in rat hippocampal slices. Exogenous activation of group I mGluRs by the selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was unable to induce LTP on its own, and instead depressed excitatory transmission. However, when paired with postsynaptic hyperpolarization, DHPG or the group I metabotropic receptor (mGluR5)-selective agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) elicited a delayed long-lasting potentiation, which was accompanied by a decrease in paired-pulse facilitation. Anti-Hebbian LTP occluded the effect of DHPG paired with hyperpolarization, implying that the induction cascades triggered by both conjunctions of stimuli converge on common expression mechanisms.

Topics: Animals; Benzoates; Electric Stimulation; Electrodes, Implanted; Electrophysiological Phenomena; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Glycine; Hippocampus; Interneurons; Long-Term Potentiation; Male; Phenylacetates; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Metabotropic Glutamate; Resorcinols

Activation of metabotropic glutamate receptors (mGluRs) modulates synaptic transmission, whereas the roles of mGluRs in GABAergic transmission in the entorhinal cortex (EC) are elusive. Here, we examined the effects of mGluRs on GABAergic transmission onto the principal neurons in the superficial layers of the EC. Bath application of DHPG, a selective Group I mGluR agonist, increased the frequency and amplitude of spontaneous IPSCs (sIPSCs) whereas application of DCG-IV, an agonist for Group II mGluRs or L-AP4, an agonist for Group III mGluRs failed to change significantly sIPSC frequency and amplitude. Bath application of DHPG failed to change significantly the frequency and amplitude of miniature IPSCs (mIPSCs) recorded in the presence of tetradotoxin but significantly reduced the amplitude of IPSCs evoked by extracellular field stimulation or in synaptically connected interneuron-pyramidal neuron pairs in layer III of the EC. DHPG increased the frequency but reduced the amplitude of APs recorded from entorhinal interneurons. Bath application of DHPG generated membrane depolarization and increased the input resistance of GABAergic interneurons. DHPG-mediated depolarization of GABAergic interneurons was mediated by inhibition of background K(+) channels which are insensitive to extracellular Cs(+), TEA, 4-AP, and Ba(2+). DHPG-induced facilitation of sIPSCs was mediated by mGluR(5) and required the function of Galphaq but was independent of phospholipase C activity. Elevation of synaptic glutamate concentration by bath application of glutamate transporter inhibitors significantly increased sIPSC frequency and amplitude demonstrating a physiological role of mGluRs in GABAergic transmission. Our results provide a cellular and molecular mechanism to explain the physiological and pathological roles of mGluRs in the EC.

Topics: Analysis of Variance; Animals; Animals, Newborn; Anticonvulsants; Benzoates; Cardiotonic Agents; Cyclopropanes; Entorhinal Cortex; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GABA Agents; gamma-Aminobutyric Acid; Glycine; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Methoxyhydroxyphenylglycol; Neural Inhibition; Neurons; Patch-Clamp Techniques; Phenylacetates; Potassium Channel Blockers; Pyrimidines; Rats; Receptors, Metabotropic Glutamate; Signal Transduction; Synaptic Transmission; Tetraethylammonium

Striatal medium spiny neurons are an important site of convergence for signaling mediated by the neurotransmitters dopamine and glutamate. We report that in striatal neurons in primary culture, signaling through group I metabotropic glutamate receptors (mGluRs) 1/5 and the D1 class of dopamine receptors (DRs) 1/5 converges to increase phosphorylation of the mitogen-activated protein kinase ERK2 (extracellular signal-regulated kinase 2). Induction of mitogen-activated protein kinase kinase-dependent signaling cascades by either mGluR1/5 or DR1/5 gave rise to increases in phosphorylation of ERK2. Coactivation of mGluR1/5 and DR1/5 with (S)-3,5-dihydroxyphenylglycine and (+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride enhanced the phosphorylation of ERK2. This interaction between mGluR1/5 and DR1/5 required protein kinase C (PKC), because the PKC inhibitors calphostin C, bisindolylmaleimide I, and Gö6976 blocked DR1/5-enhanced phosphorylation of ERK2. Use of the phosphatase inhibitors calyculin and okadaic acid indicated that inhibition of protein phosphatases 1 and 2A dramatically enhanced ERK2 phosphorylation by mGluR1/5. Coactivation of mGluR1/5 and DR1/5 also enhanced cAMP-response element binding protein (CREB) phosphorylation (compared with each receptor agonist alone) but did not enhance CREB-mediated transcriptional activity. Thus, signal transduction pathways activated by DR1/5 and mGluR5 interact to modify downstream events in striatal neurons while retaining numerous regulatory checkpoints.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Analysis of Variance; Animals; Benzazepines; Benzoates; Blotting, Western; Calcium; Cells, Cultured; Corpus Striatum; Dicarboxylic Acids; Dopamine Agonists; Dopamine Antagonists; Drug Interactions; Embryo, Mammalian; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Fluorescent Antibody Technique; Glycine; Methoxyhydroxyphenylglycol; Mitogen-Activated Protein Kinase 1; Models, Biological; Neurons; Phenylacetates; Phosphorylation; Pregnancy; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Metabotropic Glutamate; Transfection

From previous work, it appears that glutamate can activate the hypothalamic-pituitary-adrenocortical (HPA) axis by an interaction at either ionotopic or metabotropic (G-protein coupled) receptors. For example, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD), a metabotropic glutamate (mGlu) receptor agonist, has been shown to increase the levels of serum corticosterone in rats. The present study was undertaken to further characterize which of the mGlu receptors are substantially involved in control of the HPA axis. The group I mGlu receptor agonists, 3,5-dihydroxyphenylglycine (DHPG), 1S,3R-ACPD, and 2-chloro-5-hydroxyphenylglycine (CHPG) but not the inactive isomer 1R,3S-ACPD were found to dose-dependently increase serum corticosterone 1 h after intracerebroventricular (i.c.v.) injection in male rats. The relative potency, DHPG (EC50 = 520 nmol) > 1S,3R-ACPD (1.4 micromol) = CHPG (2.7 micromol) >> 1R,3S-ACPD (>> 3 micromol) is consistent with activation of group I (mGlu1/5) receptors. The effects of DHPG were long lasting with substantial elevations in corticosterone remaining for at least 3 h. In a similar manner, the group III mGlu receptor agonists, L-AP4 (4-phosphono-2-aminobutyric acid) and L-SOP (serine-O-phosphate), were found to increase serum corticosterone levels at 1 h. In contrast, the mGlu group II selective agonists LY354740 (10 mg/kg, i.p.) and subtype-selective doses of the group II antagonist LY341495 (1 mg/kg, i.p.) did not significantly elevate serum corticosterone. Given the group I agonists results, it was surprising to find that group I selective and mGlu1 selective antagonists given alone also increased serum corticosterone. As with the agonists, the rise in serum corticosterone with LY393675 (an mGlu1/5 antagonist, EC50 = 20 nmol, i.c.v.) and LY367385 (an mGlu1 antagonist, 325 nmol, i.c.v.) were dose-dependent and consistent with their relative affinity for the group I mGlu receptors. The selective mGlu5 antagonist MPEP [2-methyl-6-(phenylethylnyl)pyridine] increased serum corticosterone but only at high doses (> 30 mg/kg, i.p.). A model involving the high glutamatergic tone on GABAergic interneurons in the paraventricular nucleus of the hypothalamus is discussed as a possible explanation for these results.

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Amino Acids; Animals; Benzoates; Bridged Bicyclo Compounds; Corticosterone; Cycloleucine; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Male; Neuroprotective Agents; Paraventricular Hypothalamic Nucleus; Phenylacetates; Propionates; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Resorcinols; Xanthenes

Medium spiny neurons were recorded from striatal slices obtained from mice lacking the group I metabotropic glutamate receptor (mGluR) subtype 1 or subtype 5. In wild-type animals, N-methyl-D-aspartate (NMDA)-induced membrane depolarization/inward currents were potentiated in the presence of both the group I mGluR agonist 3,5-dihydroxyphenylglycine (3,5-DHPG) and the mGluR5 selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG). Likewise, in mGluR1 knockout mice, both 3,5-DHPG and CHPG were able to potentiate NMDA responses. Conversely, in neurons recorded from mGluR5-deficient mice, the enhancement of NMDA responses by both 3,5-DHPG and CHPG was absent. Pharmacological analysis performed from rat slices confirmed the data obtained with mice. In the presence of the competitive mGluR1 antagonist LY367385, the NMDA responses were potentiated in the presence of CHPG, whereas the CHPG-induced enhancement was not observed in slices treated with the non-competitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine. As in wild-type mice, in neither of the mGluR1- and mGluR5-deficient mice did (2S,1'R,2'R,3'R)-2-(2,3-dicarboxylcyclopropyl)-glycine (1 microM), nor L-serine-O-phosphate (30 microM) (agonists for group II and III mGluRs, respectively) affect the NMDA-evoked responses. In striatal medium spiny neurons, NMDA responses are potentiated by endogenous acetylcholine via M1-like muscarinic receptors. Since the enhancement of NMDA responses by 3,5-DHPG and by M1-like muscarinic agonists was shown to share common post-receptor mechanisms, we verified whether the muscarinic potentiation of NMDA responses was affected in these group I mGluR-deficient mice. Both in mGluR1 and mGluR5 knockout animals, in the presence of either muscarine or the M1-like muscarinic receptor agonist McN-A-343, the positive modulation of the NMDA-induced membrane depolarization persisted.These results confirm the permissive role of group I mGluRs on NMDA responses in striatal neurons and reveal that this functional interplay occurs exclusively through the mGluR5 subtype. The NMDA-mGluR5 interaction might play an important modulatory role in the final excitatory drive from corticostriatal afferents and suggests that drugs acting at mGluR5 might prove useful for the treatment of movement disorders involving the striatum.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; Action Potentials; Animals; Anticonvulsants; Benzoates; Cyclopropanes; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Mice; Mice, Knockout; Muscarine; Muscarinic Agonists; N-Methylaspartate; Neostriatum; Neurons; Phenylacetates; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Resorcinols; Synaptic Transmission

In the present study we have examined the role of presynaptic group I metabotropic glutamate (mGlu) receptors in the control of neuronal glutamate release using rat forebrain slices pre-loaded with [(3)H]D-aspartate. We have also addressed the question of which group I mGlu receptor subtype, mGlu(1) or mGlu(5), mediates the facilitatory response observed by the use of a range of established and some more novel agonists and antagonists showing selectivity for these receptors. The electrically-stimulated release of pre-loaded [(3)H]D-aspartate from rat forebrain slices was markedly potentiated by the potent group I mGlu receptor agonist, L-quisqualic acid (L-QUIS), in a concentration-dependent manner (EC(50) 17.31 microM). This response was inhibited by the mGlu receptor antagonists (S)-MCPG (100 microM) and (RS)-MTPG (100 microM) but not by the AMPA-type ionotropic glutamate receptor antagonist, NBQX (100 microM). The selective group I mGlu receptor agonist (S)-3, 5-dihydroxyphenylglycine ((S)-DHPG) also enhanced electrically-stimulated efflux of label, although responses diminished with high (10-100 microM) concentrations of the agonist. Maximum responses were fully restored when (S)-DHPG (10 microM) was applied in the presence of the proposed mGlu(5) receptor desensitization inhibitor, cyclothiazide (10 microM). The positive modulatory response to (S)-DHPG (1 microM) was powerfully inhibited by (S)-MCPG (IC(50) 0.08 microM) but was resistant to the mGlu(1) receptor antagonists, (RS)-AIDA (1-500 microM), CPCCOEt (0.1-100 microM) and (+)-2-methyl-4-carboxyphenylglycine (LY367385) (0.1-10 microM). The recently developed, selective mGlu(5) receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine ((RS)-CHPG) enhanced electrically-stimulated [(3)H]D-aspartate efflux from rat forebrain slices with a similar concentration-response profile to that of (S)-DHPG. Responses to this receptor subtype-selective agonist were also blocked by (S)-MCPG (IC(50) 1.13 microM) but were unaffected by (RS)-AIDA (500 microM), CPCCOEt (100 microM) or LY367385 (10 microM). These results indicate that the positive modulation of neuronal glutamate release seen in the rat forebrain in the presence of group I mGlu receptor agonists is mediated by presynaptically located mGlu(5) glutamate autoreceptors. The pharmacological profile of these receptors appears to be distinct from that of postsynaptic mGlu receptors. Novel antagonists acting at these presynaptic receptors may provide new drugs

Topics: Animals; Aspartic Acid; Autoreceptors; Benzoates; Calcium; Dose-Response Relationship, Drug; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; In Vitro Techniques; Indans; Male; Neurons; Phenylacetates; Prosencephalon; Quisqualic Acid; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Resorcinols; Tetrodotoxin; Tritium