AGE-RELATED-CHANGES IN NMDA-INDUCED [H-3] ACETYLCHOLINE-RELEASE FROM BRAIN-SLICES OF SENESCENE-ACCELERATED MOUSE

From the brain slices of normal mice (ddY strain, subcloned from dd strain in National Institute of Health in Japan), N-methyl-D-aspartic acid (NMDA) at 0.01 approximately 1 mM evoked [H-3]acetylcholine (ACh) release in a concentration dependent manner. [H-3]ACh release evoked by 1 mM NMDA was significantly inhibited by 2-amino-5-phosphonovaleric acid (APV), phencyclidine (PCP) and 5-methyl-10,11-dihydroxy-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801). The effects of NMDA were not seen in the Ca2+ free medium and were inhibited by physiological concentration (0.83 mM) of Mg2+. NMDA seems to cause ACh release from nerve terminals through the receptor-ion channel mediated mechanism in the mouse brain. Based upon these results, we determined the activity of a high K+- or NMDA-evoked [H-3]ACh release using prone/8 strain of senescence-accelerated mouse (SAM-P/8) (a murine model of accelerated aging and memory dysfunction) and SAM-resistance/1 strain (SAM-R/1) (normal aging mice as the control) and these release activities were compared between both strains and during aging. [H-3]ACh release evoked by 30 mM KCl was significantly lower than that of age-matched SAM-R/I at 9 and 12 months. NMDA evoked the [H-3]ACh release at 2, 6, 10 and 14 months in R/1 mice. In SAM-P/8 mice the activity of NMDA-evoked release was seen at 2 months, but markedly decreased afterwards. Nonsignificant difference was observed on the uptake of [H-3]choline and on the spontaneous release of [H-3]ACh between SAM-P/8 and SAM-R/1 strains, and during aging. These results suggest: (1) NMDA receptor-ion channels are involved in the ACh release from nerve terminals in the CNS; (2) the NMDA-evoked ACh release is decreased after 6 months in SAM-P/8 mice but not in SAM-R/1 mice; and (3) the high K+-evoked ACh release is decreased at an earlier age in SAM-P/8 than it is in SAM-R/1. These results suggest that the NMDA- and cholinergic-system in the CNS seems to be deficient in SAM-P/8 and that this deterioration may be a possible cause for their dysfunction of learning and memory.