4-aminopyrrolidine-2-4-dicarboxylic-acid and 3-5-dihydroxyphenylglycine

This study was performed to investigate the ameliorative effects of metabotropic glutamate (mGlu)-receptor agonists on histamine H(1) receptor antagonist-induced spatial memory deficit and the decrease in hippocampal theta activity in rats. Intraperitoneal injection of pyrilamine (35 mg/kg) resulted in impaired reference and working memory in the radial maze task and decreased hippocampal theta amplitude and power. The working memory deficit and decreased hippocampal theta power induced by pyrilamine were ameliorated by intrahippocampal injection of (RS)-3,5-dihydroxyphenylglycine (DHPG) (1 and 10 microg/side), a group I mGlu-receptor agonist; however, intrahippocampal injection of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC), a group II mGlu-receptor agonist, and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), a group III mGlu-receptor agonist, showed no significant effect on the pyrilamine-induced memory deficit and decreased hippocampal theta activity. These results indicate that the activation of hippocampal group I mGlu receptors, but not group II and III mGlu receptors, improve the histamine H(1) receptor antagonist-induced working memory deficit and decreased hippocampal theta activity.

Topics: Aminobutyrates; Animals; Drug Interactions; Excitatory Amino Acid Agonists; Glycine; Hippocampus; Histamine H1 Antagonists; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Proline; Pyrilamine; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Resorcinols; Theta Rhythm

The potential role of metabotropic glutamate (mGlu) receptors in cardiovascular function in the nucleus of the solitary tract was examined following the microinjection of a number of selective mGlu receptor compounds into this site of anaesthetized rats. The prototypic mGlu receptor selective agonist 1S,3R-1-amino-cyclopentane dicarboxylate elicited depressor and bradycardic actions following microinjection into the nucleus tractus solitarius, which were similar to those produced by L-glutamate. Similarly, decreases in blood pressure and heart rate were observed upon administration of the type I and II selective mGlu receptor agonists, (R,S)-3,5-dihydroxyphenylglycine (DHPG) and 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC), respectively. These actions of DHPG were selectively attenuated by (+/-)-1-aminoindane-1,5-dicarboxylate, a type I mGlu receptor antagonist, whilst cardiovascular responses to APDC were unaffected by this compound. Interestingly, the proposed type II antagonist, (2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-doic acid, reduced the cardiovascular responses to intra-nucleus tractus solitarius administration of both APDC and DHPG. The type III mGlu receptor agonist, L-2-amino-4-phosphonobutyrate, however, failed to elicit any cardiovascular actions when microinjected into the nucleus tractus solitarius. These studies provide new evidence for functional type I and II mGlu receptors in modulating cardiovascular responses in the nucleus tractus solitarius.

Topics: Anesthesia; Animals; Blood Pressure; Bradycardia; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Heart Rate; Indans; Male; Microinjections; Proline; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Resorcinols; Solitary Nucleus

The mGlu receptor subtypes and second messenger pathways that mediate 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) responses in brain tissues are not fully understood. 1S,3R-ACPD differs from 3,5-dihydroxyphenylglycine (DHPG) or quisqualate in that 1S,3R-ACPD also activates group 2 mGlu receptors (mGlu2 and mGlu3) that are negatively linked to cAMP formation. To investigate the contribution of group 2 mGlu receptor activity of 1S,3R-ACPD to the phosphoinositide response in the rat hippocampus, we examined the effects of the novel group 2 mGlu receptor agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC). 2R,4R-APDC did not activate or inhibit group 1 mGlu receptors (human mGlu1 alpha and mGlu5a) or group 3 mGlu receptors (human mGlu4 and mGlu7), but potently decreased forskolin-stimulated cAMP formation in human mGlu2- and mGlu3-expressing cells. In slices of the adult rat hippocampus 2R,4R-APDC had no effect on basal phosphoinositide hydrolysis; however, it was found to greatly enhance phosphoinositide hydrolysis to DHPG or quisqualate. In the neonatal rat hippocampus, 2R,4R-APDC enhanced the potency of DHPG, while not affecting the maximal response to group 1 mGlu receptor agonists. Thus, the phosphoinositide response in the rat hippocampus to 1S,3R-ACPD is mediated by a synergistic interaction between group 1 and group 2 mGlu receptors.

Topics: Aging; Animals; Animals, Newborn; Brain; Cloning, Molecular; Colforsin; Cyclic AMP; Cycloleucine; Drug Synergism; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Hippocampus; Humans; Inositol; Kinetics; Neuroprotective Agents; Phosphatidylinositols; Proline; Quisqualic Acid; Rats; Receptors, Metabotropic Glutamate; Recombinant Proteins; Resorcinols; Second Messenger Systems