Oxiracetam prevents the hippocampal cholinergic hypofunction induced by the NMDA receptor blocker AP7.
The intracerebroventricular injection of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-7-phosphonoheptanoic acid (AP7) induces an increase of the hippocampal levels of acetylcholine (ACh) which is dose-dependent in the range 1.5-10 micrograms. Similar doses of AP7 failed to affect the ACh content of the striatum. The effect of the i.c.v. administration of 3.5 micrograms AP7 on hippocampal ACh levels was prevented by pretreatment with oxiracetam 100 mg/kg i.p. In the passive avoidance test the i.c.v. administration of 3.5 micrograms of AP7 caused severe amnesia which was antagonized in a dose-dependent manner by the pretreatment with oxiracetam. These results show that oxiracetam prevents the imbalance of cholinergic activity and the amnesia caused by blockade of NMDA receptors. The present study suggests that the hippocampal cholinergic activity is modulated by glutamatergic neuronal pathways and that the functional integrity of both systems is essential for learning and memory processes.
Belfiore
P
P
ISF-Laboratories for Biomedical Research, Trezzano s/N, Milan, Italy.
Ponzio
F
F
Biagetti
R
R
Berettera
C
C
Magnani
M
M
Pozzi
O
O
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000109:Acetylcholine / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012153:Retention, Psychology / Q000187:drug effects
D000596:Amino Acids; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate; D015763:2-Amino-5-phosphonovalerate; D000109:Acetylcholine; C031231:2-amino-7-phosphonoheptanoic acid; C040619:oxiracetam