EFFECTS OF ANTAGONISTS ON QUISQUALATE AND NICOTINIC RECEPTOR-MEDIATED CURRENTS OF MIDBRAIN NEURONS IN CULTURE

1 The action of non-N-methyl-D-aspartate (non-NMDA) and nicotinic antagonists on excitatory post-synaptic currents (e.p.s.cs) and on quisqualate (Quis)- and nicotine-gated currents was studied by use of whole-cell recording in dissociated culture of the rat midbrain. 2 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX; 0.1-mu-M) and kynurenic acid (0.1 mM) attenuated network-generated and miniature e.p.s.cs while mecamylamine (100-mu-M) and hexamethonium (400-mu-M) had no effect. Acetylcholine (ACh) enhanced or suppressed e.p.s.cs. The suppressing effect of ACh was blocked by atropine (0.1-10-mu-M). 3 ACh (50-1000-mu-M) and quisqualate (Quis, 0.1-20-mu-M) induced inward currents with the same reversal potential as e.p.s.cs. 4 Application of Quis and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) in a low concentration (0.5 and 5-mu-M, respectively) evoked a maintained current which was attenuated by CNQX (1-mu-M) and kynurenic acid (0.5 mM) but not by mecamylamine (100-mu-M). 5 Higher concentrations of Quis (5-20-mu-M) and AMPA (50-100-mu-M) evoked a transient and a maintained current component. Kynurenic acid (1 mM) reduced the transient but not the maintained component. CNQX (5-10-mu-M) increased the maintained component without reducing the transient one; 20-mu-M CNQX reduced both components. 6 ACh-induced transient current was mimicked by nicotine and reversibly and dose-dependently blocked by mecamylamine. Atropine (10-mu-M), hexamethonium (400-mu-M) as well as CNQX (100-mu-M) and kynurenic acid (1 mM) did not affect the current. 7 Hexamethonium (50-400-mu-M) voltage-dependently depressed the maintained current elicited by both Quis and ACh. 8 In conclusion, although the antagonists examined here seem to discriminate between non-NMDA and nicotinic receptor-mediated e.p.s.cs, they vary considerably in respect of their mode of action when tested on Quis, AMPA and ACh-induced currents.