The effect of L-NAME and L-arginine on impairment of memory formation and state-dependent learning induced by morphine in mice

Rationale: Morphine and nitric oxide (NO) have important functional interactions in different neural processes, and both modulate learning and memory although their interaction in cognitive performance has not been elucidated. Objective: To examine the effect of the NO synthase (NOS) inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) and NOS substrate L-arginine on morphine-induced impairment of memory formation and the state-dependent retrieval of a passive avoidance task learned under morphine influence. Methods: All drugs were administered intraperitoneally, and a one-trial step-down paradigm was used for the assessment of memory in adult male NMRI mice. Morphine was administered 30 min before training to induce impairment of memory formation and 30 min before test to induce state-dependent retrieval of the memory acquired under pretraining morphine influence. L-NAME or L-arginine was administered either 5 min after training or 45 min before the test. Results: Pre-training morphine induced impairment of memory formation that was reversible by pre-test morphine but not saline. Post-training administration Of L-arginine (200 mg/kg) and L-NAME (3, 10 and 30 mg/kg), respectively, facilitated and impaired the memory consolidation, but their pre-test injections did not affect retention. However, post-training L-arginine at per se non-effective doses of 20 mg/kg and 60 mg/kg reversed the morphine-induced impairment of memory formation. Pretest administration Of L-NAME (3 mg/kg and 10 mg/kg) could restore the memory impairment induced by pretraining morphine, and this effect was blocked by concomitant pre-test L-arginine (60 mg/kg). Concomitant administration of low doses Of L-NAME (1 mg/kg) and morphine (0.5 mg/kg) pre-test also revealed an additive effect in restoring the morphine state of memory. Conclusion: These results suggest that the impairment of memory formation and the facilitation of retrieval induced by morphine involves decreased synthesis/release of NO and can be counteracted by NOS substrate.