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Group II metabotropic glutamate receptors are a common target of N-anisoyl-GABA and 1S,3R-ACPD in enhancing ACh release in the prefrontal cortex of freely moving SHRSP.

Abstract
Aniracetam is a therapeutically useful cognition enhancer for treating various neuropsychiatric symptoms occurring after cerebral infarction. We recently reported that local perfusion of its major metabolites N-anisoyl-GABA and p-anisic acid, but not aniracetam itself, enhanced acetylcholine (ACh) release with a delayed onset in cerebral regions of stroke-prone spontaneously hypertensive rats (SHRSP). In this study, we examined the possible involvement of metabotropic and ionotropic glutamate (mGlu and AMPA) receptors in the N-anisoyl-GABA-induced ACh release using brain in vivo microdialysis. Basal ACh release in SHRSP was commonly lower in the nucleus reticularis thalami, dorsal hippocampus and prefrontal cortex than that in age-matched Wistar Kyoto rats. The delayed ACh release in the prefrontal cortex of SHRSP was completely blocked by MCPG, a group I and II mGlu receptor antagonist, and MCCG, a group II-selective mGlu receptor antagonist. In contrast, it was largely unaffected by AIDA, a group I-selective mGlu receptor antagonist, or by YM90K, an AMPA receptor antagonist. 1S,3R-ACPD, a preferential group II mGlu receptor agonist, enhanced ACh release with a similar latency and the effect was antagonized by MCCG, whereas AMPA induced a prompt ACh release. These results indicate that N-anisoyl-GABA and 1S,3R-ACPD share a common mechanism mediated by group II mGlu receptors in enhancing ACh release. The findings suggest a possible mechanism for aniracetam's clinical efficacy in stroke patients with cholinergic deficits.
AuthorsM Shirane, K Nakamura
JournalNeuropharmacology (Neuropharmacology) Vol. 39 Issue 5 Pg. 866-72 (Mar 03 2000) ISSN: 0028-3908 [Print] England
PMID10699452 (Publication Type: Journal Article)
Chemical References
  • 1-aminoindan-1,5-dicarboxylic acid
  • 2-methyl-2-(2-carboxycyclopropyl)glycine
  • Amino Acids, Dicarboxylic
  • Anisoles
  • Benzoates
  • Excitatory Amino Acid Antagonists
  • Indans
  • Quinoxalines
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Cycloleucine
  • 1-amino-1,3-dicarboxycyclopentane
  • alpha-methyl-4-carboxyphenylglycine
  • 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione
  • N-anisoyl-GABA
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Acetylcholine
  • Glycine
Topics
  • Acetylcholine (metabolism)
  • Amino Acids, Dicarboxylic (pharmacology)
  • Animals
  • Anisoles (administration & dosage)
  • Benzoates (pharmacology)
  • Cycloleucine (administration & dosage, analogs & derivatives)
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists (pharmacology)
  • Glycine (analogs & derivatives, pharmacology)
  • Hippocampus (drug effects, metabolism)
  • Indans (pharmacology)
  • Male
  • Microdialysis
  • Perfusion
  • Prefrontal Cortex (drug effects, metabolism)
  • Quinoxalines (pharmacology)
  • Rats
  • Rats, Inbred SHR
  • Receptors, AMPA (agonists, antagonists & inhibitors)
  • Receptors, Metabotropic Glutamate (agonists, antagonists & inhibitors, drug effects, metabolism)
  • Thalamic Nuclei (drug effects, metabolism)
  • Wakefulness
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (metabolism, pharmacology)

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