Effects of the nitric oxide synthase inhibitor L-NAME on recognition and spatial memory deficits produced by different NMDA receptor antagonists in the rat

Abstract

There is consistent experimental evidence that noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, such as ketamine, MK-801, and phencyclidine (PCP), impair cognition and produce psychotomimetic effects in rodents. Nitric oxide (NO) is considered as an intracellular messenger in the brain. The implication of NO in learning and memory is well documented. This study was designed to investigate the ability of the NO synthase inhibitor L-NAME to antagonize recognition and spatial memory deficits produced by the NMDA receptor antagonists, MK-801 and ketamine, in the rat. L-NAME (1-3 mg/kg) counteracted MK-801- (0.1 mg/kg) and ketamine (3 mg/kg)-induced performance impairments in the novel object recognition task. L-NAME (10 mg/kg) attenuated ketamine (15 mg/kg)-induced spatial working memory and retention deficits in the radial water maze paradigm. L-NAME, applied at 3 mg/kg, however, disrupted rodents' performance in this spatial memory task. The present findings indicate (1) that L-NAME is sensitive to glutamate hypofunction produced by other than PCP NMDA antagonists such as MK-801 and ketamine and (2) that L-NAME alone differentially affects rodents' spatial memory.

Figure 1

Novel object recognition task. Vehicle, MK-801, and -NAME were injected i.p., just after T1. The 3-h ITI was used. Results are expressed as mean±SEM. Discrimination index D performance expressed by different groups of rats during T2. ^*p<0.05 vs all the other groups (except the MK-801+-NAME 10 mg/kg group); ⁺p<0.05 vs all the other groups (except the MK-801+vehicle group).

Figure 2

Novel object recognition task. Vehicle, ketamine, and -NAME were injected i.p., just after T1. The 1-h ITI was used. Results are expressed as mean±SEM. Discrimination index D performance expressed by different groups of rats during T2. ^*p<0.05 vs all the other groups (except the ketamine+-NAME 10 mg/kg group); ⁺p<0.05 vs all the other groups (except the ketamine+vehicle group).

Figure 3

Radial water maze task. Vehicle and -NAME were injected i.p., every day 60 min before testing. (a) Spatial reference memory. Results are expressed as mean±SEM. Number of errors cumulating over days by different groups of rats. (b) Spatial working memory. Results are expressed as mean±SEM. Number of errors cumulating over days by different groups of rats. (c) Percentage of total time spent in the previously reinforced arm of the radial water maze by different groups of rats. Results are expressed as medians. ^*p<0.05 vs the vehicle-treated animals.

Figure 4

Radial water maze task. Vehicle, ketamine, and -NAME were injected i.p., every day 40 and 60 min, respectively, before testing. (a) Spatial reference memory. Results are expressed as mean±SEM. Number of errors cumulating over days by different groups of rats. (b) Spatial working memory. Results are expressed as mean±SEM. Number of errors cumulating over days by different groups of rats. (c) Percentage of total time spent in the previously reinforced arm of the radial water maze by different groups of rats. Results are expressed as medians. ^*p<0.05 vs the vehicle+vehicle-treated animals; ⁺p<0.05 vs the respective control populations; ^#p<0.05 vs ketamine+-NAME 10 mg/kg-treated rats.