Concurrent activation of hippocampal glycine and polyamine sites of the N-methyl-D-aspartate receptor synergistically reverses working memory deficits in rats.
Intrahippocampal administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (0.18 microg/side) significantly increased the number of errors in the working memory task with a three-panel runway setup. The increase in working memory errors by intrahippocampal MK-801 was significantly attenuated by concurrent infusion of D-cycloserine (1.0 microg/side) or spermidine (10 microg/side), agonists of the glycine and polyamine modulatory sites on the NMDA receptor/channel complex, respectively. Combined injection of the behaviorally ineffective doses of 0.1 microg/side D-cycloserine and 0.32 microg/side spermidine synergistically reduced intrahippocampal MK-801-induced increase in working memory errors. The combination of D-cycloserine and spermidine also synergistically attenuated the increase in working memory errors resulting from intrahippocampal injection of the muscarinic acetylcholine receptor antagonist scopolamine (3.2 microg/side). These results suggest that positive modulation of the NMDA receptor/channel through activation of the glycine and polyamine sites can synergistically compensate deficiency of hippocampal NMDA and muscarinic receptor-mediated neurotransmission involved in working memory function.
Kishi
A
A
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Ohno
M
M
Watanabe
S
S
D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003523:Cycloserine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000009:adverse effects; D004357:Drug Synergism; D005998:Glycine / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013095:Spermidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D000963:Antimetabolites; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003523:Cycloserine; D005998:Glycine; D013095:Spermidine