Lithium chloride disrupts consolidation of morphine-induced conditioned place preference in male mice: the nitric oxide/cyclic GMP signaling pathway.

Lithium effects on brain functions such as cognition, attention, learning and memory are well-established for ages; however, the way it affects these functions and its precise mechanism of action remains unknown. The purpose of this study was to determine the effects of lithium on the consolidation of morphine-associated conditioned place preference and the possible involvement of the NO/cGMP pathway. Using an unbiased conditioned place preference (CPP) model, the effects of lithium (1-100 mg/kg, i.p.), nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (5-100 mg/kg, i.p.), nitric oxide precursor L-arginine (50-150 mg/kg, i.p.) and phosphodiesterase inhibitor sildenafil (5-40 mg/kg, i.p.) on the consolidation of morphine-induced CPP were assessed. In addition, the possible interaction between lithium, L-arginine and sildenafil or subeffective doses of lithium and L-NAME on the consolidation of morphine-induced contextual memory was evaluated. NMRI mice were used in all studies. Lithium (5-30 mg/kg, i.p.), immediately after conditioning trials, significantly reduced the time spent by mice in the reward-paired compartment. Although post-training administration of L-arginine, sildenafil or L-NAME had no significant effect on the consolidation of CPP, concomitant administration of L-arginine (50-150 mg/kg) and sildenafil (5-10 mg/kg) with lithium (30 mg/kg) prevented the impairing effect of lithium. Also, co-administration of sub-effective doses of lithium (1 mg/kg) and L-NAME (5 mg/kg) disrupted consolidation of CPP. However, delayed administration of effective doses of lithium, which shows specific effect on memory consolidation, did not affect morphine-induced CPP. Lithium seems to inhibit consolidation of morphine-induced CPP and this impairing effect might be via nitric oxide/cyclic GMP pathway.