Concurrent blockade of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors disrupts working memory in the rat.
In order to clarify the roles of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors in working and reference memory performance of rats, the effects of intrahippocampal administration of selective antagonists for both receptors on these behaviours were examined with a three-panel runway task. In the working memory task, the potent and competitive N-methyl-D-aspartate receptor antagonist, (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), when injected bilaterally at 10 and 32 ng/side into the dorsal hippocampus. Intrahippocampal injection of CPP at a dose of 3.2 ng/side had no effect on the number of working memory errors. The metabotropic glutamate receptor antagonist, (+)-alpha-methyl-4-carboxyphenylglycine (+)-(MCPG), injected into the hippocampus at doses up to 3.2 micrograms/side, did not significantly affect the number of working memory errors. Combined administration of (+)-MCPG (3.2 micrograms/side) and CPP (3.2 ng/side) into the hippocampus, neither of which had an individual effect on errors, significantly increased the number of working memory errors. However, intrahippocampal administration of the relatively inactive isomer, (-)-MCPG, at 3.2 micrograms/side did not affect working memory errors, whether given independently or concurrently with the behaviourally ineffective dose of CPP (3.2 ng/side). In the reference memory task, intrahippocampal injection of CPP at doses up to 32 ng/side had no effect on the number of errors. Intrahippocampal (+)-MCPG at doses up to 3.2 micrograms/side did not affect the number of reference memory errors, whether administered alone or together with 3.2 ng/side of CPP. These results indicate that blockade of hippocampal metabotropic glutamate receptors aggravates impairment of working memory resulting from deficiency of N-methyl-D-aspartate receptor-mediated glutamatergic neurotransmission, suggesting that mechanisms regulated by co-activation of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors are involved in working memory performance of rats.
Ohno
M
M
Department of Pharmacology, Kyushu University, Fukuoka, Japan.
Watanabe
S
S
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D063065:Organophosphonates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D063065:Organophosphonates; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate