IMPAIRED LEARNING IN RATS IN A 14-UNIT T-MAZE BY 7-NITROINDAZOLE, A NEURONAL NITRIC-OXIDE SYNTHASE INHIBITOR, IS ATTENUATED BY THE NITRIC-OXIDE DONOR, MOLSIDOMINE

In previous experiments, it was demonstrated that systemic or central administration of the nitric oxide synthase (NO synthase) inhibitor, N -G-nitro-L-arginine (N-Arg), produced dose-dependent learning impairme nts in rats in a 14-unit T-maze; and that sodium nitroprusside, a NO d onor, could attenuate the impairment. Since N-Arg is not specific for neuronal NO synthase and produces hypertension, it is possible that ef fects on the cardiovasculature may have contributed to the impaired ma ze performance. In the present experiment, we have investigated the ma ze performance of 3-4 months old male Fischer-344 rats following treat ment with 7-nitroindazole, a NO synthase inhibitor that is selective f or neuronal NO synthase and does not produce hypertension. In addition , we examined the effects of the NO donor, molsidomine, which is much longer acting than sodium nitroprusside. Rats were pretrained to avoid footshock in a straight runway and received training in a 14-unit T-m aze 24 h later. In an initial dose-response study: rats received intra peritoneal (i.p.) injections of either 7-nitroindazole (25, 50, or 65 mg/kg) or peanut oil 30 min prior to maze training. 7-nitroindazole pr oduced significant, dose-dependent maze acquisition deficits, with 65 mg/kg producing the greatest learning impairment. This dose of 7-nitro indazole had no significant effect on systolic blood pressure. Followi ng the dose-response study, rats were given i.p. injections of either 7-nitroindazole (70 mg/kg) plus saline, 7-nitroindazole (70 mg/kg) plu s the NO donor, molsidomine (2 or 4 mg/kg), or peanut oil plus saline as controls. Both doses of molsidomine significantly attenuated the le arning deficit induced by 7-nitroindazole relative to controls. These findings represent the first evidence that impaired learning produced by inhibition of neuronal NO synthase can be overcome by systemic admi nistration of a NO donor. (C) 1998 Elsevier Science B.V.