Reversal of chlorpromazine-induced avoidance depression by the N-methyl-D-aspartate antagonist, dizocilpine, in mice.

The non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 (dizocilpine) was tested, alone or in combination with chlorpromazine, in mice previously trained in the shuttlebox. The lowest doses of dizocilpine (0.02 and 0.04 mg kg-1) attenuated the disrupting action of the neuroleptic (1.5 mg kg-1) on avoidance-performance, while avoidance depression induced by 1.5 and 2 mg kg-1 chlorpromazine was completely or almost completely reversed by 0.08 mg kg-1 NMDA antagonist. The highest dose (0.16 mg kg-1) of dizocilpine did not ameliorate avoidance-performance of mice receiving 2 mg kg-1 chlorpromazine, perhaps because of ataxic effects produced by the drug combination, at these doses. The results support suggestions for a potential use of NMDA antagonists in the treatment of extrapyramidal side-effects of neuroleptics.