NMDA AND NON-NMDA IONOTROPIC GLUTAMATE RECEPTORS MODULATE STRIATAL ACETYLCHOLINE-RELEASE VIA PRE-SYNAPTIC AND POSTSYNAPTIC MECHANISMS

The effects of NMDA and cu-amino-3-hydroxy5-methylisoxazole-4-propioni c acid (AMPA) on endogenous acetylcholine release from rat striatal sl ices and synaptosomes were investigated. Both agonists (1-300 mu M) fa cilitated acetylcholine release from slices in a dose-dependent manner . NMDA (100-300 mu M) and AMPA (30-300 mu M), however, subsequently in hibited acetylcholine release. NMDA(100 mu M)-induced facilitation was antagonized by 3- (2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ( CPP) and dizocilpine (both 1-10 mu M), whereas the 10 mu M AMPA effect was antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1-30 m u M). NMDA (100 mu M)-induced inhibition was counteracted by CPP, but not dizocilpine, and by the nitric oxide synthase inhibitor L-nitroarg inine (1-100 mu M). Tetrodotoxin (0.5 mu M) prevented the facilitatory effect of 3 mu M NMDA and AMPA, but left unchanged that of 30 mu M NM DA and 100 mu M AM PA. Acetylcholine release from synaptosomes was sti mulated by KCI (7.5-100 mM) in a dose-dependent manner. NMDA and AMPA maximally potentiated the 20 mM KCI effect at 1 mu M and 0.01 mu M, bu t were ineffective at 100 mu M and 10 mu M, respectively. Inhibition o f acetylcholine release was never found in synaptosomes. The effects o f 1 mu M NMDA and 0.01 mu M AMPA were antagonized by CPP (0.0001-1 mu M) or dizocilpine (0.0001-10 mu M) and by CNQX (0.001-1 mu M), respect ively. These data suggest that glutamatergic control of striatal acety lcholine release is mediated via both pre- and postsynaptic NMDA and n on-NMDA ionotropic receptors.