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.
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.
Shirane
M
M
CNS Supporting Laboratory, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Japan.
Nakamura
K
K
D000109:Acetylcholine / Q000378:metabolism*; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D000840:Anisoles / Q000008:administration & dosage*; D001565:Benzoates / Q000494:pharmacology; D003515:Cycloleucine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D010477:Perfusion; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D013787:Thalamic Nuclei / Q000187:drug effects / Q000378:metabolism; D014851:Wakefulness; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism / Q000494:pharmacology
C095756:1-aminoindan-1,5-dicarboxylic acid; C089837:2-methyl-2-(2-carboxycyclopropyl)glycine; D000600:Amino Acids, Dicarboxylic; D000840:Anisoles; D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D011810:Quinoxalines; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C079694:alpha-methyl-4-carboxyphenylglycine; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione; C067664:N-anisoyl-GABA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000109:Acetylcholine; D005998:Glycine