8-bromocyclic-gmp and 1-amino-1-3-dicarboxycyclopentane

1. Facilitation of the N-methyl-D-aspartate (NMDA) receptor-mediated depolarization of cortical neurones induced by metabotropic glutamate receptor (mGluR) agonists in the presence of tetrodotoxin has been examined by use of grease-gap recording. 2. Quisqualate (1-2 microM) and 10 to 100 microM 1S,3R-I-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) facilitated the NMDA-, but not the kainate-induced depolarization with an EC50 of 16 microM for 1S,3R-ACPD. The facilitation induced by quisqualate was reduced, but not blocked, by 4 microM 6-cyano-7-nitroquinoxaline-2,3-dione. 3. D,L-2-Amino-3-phosphonopropionic acid and D,L-2-amino-4-phosphonobutyric acid antagonized the 1S,3R-ACPD facilitation in a non-competitive manner with IC50 values of 0.24 microM and 4.4 microM respectively. 4. Homologous desensitization of the 1S,3R-ACPD induced facilitation was not observed. The facilitation was not altered by 10 nM staurosporine or 3 microM phorbol diacetate. 5. Substitution of 20 microM 8-bromo-cyclic adenosine monophosphate, 20 microM 8-bromo-cyclic guanosine monophosphate, or 10 microM arachidonic acid for 1S,3R-ACPD did not induce facilitation of the NMDA response. However, the 1S,3R-ACPD facilitation was potentiated by 10 mM myo-inositol and exhibited heterologous desensitization following exposure to 100 microM 5-hydroxytryptamine. 6. The 1S,3R-ACPD-induced facilitation persisted in both 10 microM nifedipine and nominally Ca(2+)-free medium and was only gradually eliminated following addition of 100 microM bis-(-o-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid in Ca(2+)-free medium. Facilitation of the NMDA response induced by carbachol, but not phenylephrine, was also observed in nominally Ca(2+)-free medium. Perfusing 50 microM bis-(-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid aminoethoxy eliminated the 1S,3R-ACPD facilitation. 7. These experiments have shown that mGluR agonists selectively facilitate the NMDA depolarization of cortical wedges, most likely by activating one or more mGluR subtypes that couple to phospholipase C. We conclude the facilitation results from a Ca(2+)-sensitive mechanism dependent on activation of phospholipase C and release of internal Ca2+. The facilitation is not contingent on activation of protein kinase C or entry of Ca2+ through nifedipine-sensitive Ca2+ channels.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Alanine; Alkaloids; Aminobutyrates; Animals; Cerebral Cortex; Cyclic GMP; Cycloleucine; Male; Neurons; Phorbol Esters; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Staurosporine

In rat cerebellar slices, 500 microM (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) reversibly inhibited both dendritic and somatic increases in FLUO-3 fluorescence intensity induced by bath applications of 50-100 microM (+-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD). No effect of MCPG was observed on dendritically recorded excitatory postsynaptic potentials evoked by synaptic activation of either parallel or climbing fibres. Long-term depression of parallel fibre-Purkinje cell transmission, induced either by conjunctive activation of parallel and climbing fibres or by pairing parallel fibre stimulation with intradendritic injections of 8-BrcGMP, was not only prevented in the presence of MCPG but a robust long-term potentiation of responses consistently occurred. These data show that metabotropic glutamate receptor activation is necessary for the induction of LTD.

Topics: Aniline Compounds; Animals; Benzoates; Biotransformation; Cerebellum; Cyclic GMP; Cycloleucine; Cyclopropanes; Evoked Potentials; Fluorescent Dyes; Glycine; In Vitro Techniques; Nerve Fibers; Neuronal Plasticity; Neurotoxins; Purkinje Cells; Rats; Receptors, Metabotropic Glutamate; Synaptic Transmission; Xanthenes

The effects of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] on ionic current responses produced by ionotropic glutamate and gamma-aminobutyric acid (GABA)A receptor activation in the nucleus of the tractus solitarius (NTS) were examined. Recordings were made in the dorsomedial subdivision of the NTS adjacent to the area postrema in transverse brainstem slices of the rat. (1S,3R)-ACPD produced a small inward current (IACPD) associated with a decrease in conductance in approximately 50% of recordings. Monosynaptic excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation in the region of the tractus solitarius in the presence of D-amino-5-phosphonopentanoic acid and bicuculline were reversibly reduced by (1S,3R)-ACPD in > 90% of cells. The inward current evoked by pressure application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (IAMPA) was potentiated in the presence of (1S,3R)-ACPD, whereas the outward current evoked by the GABAA receptor agonist muscimol (IMUSC) was inhibited. We have previously demonstrated that these effects may involve the activation of soluble guanylate cyclase. The diffusible second messengers nitric oxide and carbon monoxide are known to activate soluble guanylate cyclase. The nitric oxide synthase inhibitor L-omega-nitroarginine failed to inhibit responses to (1S,3R)-ACPD. The selective heme oxygenase inhibitor Zn-protoporphyrin-IX, which would be expected to block the production of carbon monoxide, antagonized the effects of (1S,3R)-ACPD on EPSCs, IAMPA, and IMUSC. However, IACPD was not blocked. A relatively inactive metalloprotoporphyrin, Cu-protoporphyrin-IX was ineffective. A cell-permeant form of cGMP, 8-Br-cGMP inhibited EPSCs, IAMPA, and IMUSC in the presence of Zn-protoporphyrin-IX but did not induce an inward current. These results further support the hypothesis that multiple metabotropic glutamate receptors exist in the NTS, and they suggest that one of these may be coupled to the activation of a soluble guanylate cyclase via the liberation of an easily diffusible second messenger such as carbon monoxide.

Topics: Action Potentials; Animals; Brain Stem; Cyclic GMP; Cycloleucine; Electrophysiology; Heme Oxygenase (Decyclizing); Neurotoxins; Protoporphyrins; Rats; Receptors, GABA-A; Receptors, Glutamate