Introduction: Pioglitazone, a PPAR-γ agonist, which is clinically used in treating diabetic patients, has been recently reported to have crucial roles in improving cognition and memory performance. Since the mechanisms involved in the neuroprotective effect of pioglitazone are not entirely understood, the current study was designed to investigate the possible interaction of pioglitazone with morphine in memory-impaired mice and the probable role of nitric oxide (NO) in this effect.

Materials and methods: All the experiments were performed in passive avoidance and Y-maze paradigms. To induce memory impairment, mice were administered morphine (1, 3 and 10mg/kg, s.c.) immediately before the training trial. Pioglitazone (20, 40 and 80mg/kg, p.o.) was gavaged 2h prior to the training trial. Further, an NO synthase inhibitor, L-NAME (10mg/kg, i.p.), or an inducible NO synthase inhibitor, aminoguanidine (100mg/kg, i.p.) was administered 30 min before the training trial to determine the possible involvement of NO in the restorative effect of pioglitazone.

Results: 1) Morphine dose dependently impaired the acquisition of spatial memory and passive avoidance task. 2) Treatment with pioglitazone significantly improved the memory performance in morphine-treated mice in both tests. 3) In the passive avoidance task, L-NAME, but not aminoguanidine, altered the effect of pioglitazone on morphine-induced memory impairment. 4) In Y-maze discrimination, the memory improving effect of pioglitazone was reversed by both NO synthase inhibitors, L-NAME and aminoguanidine.

Discussion: Our results demonstrate that the pioglitazone improving effect on the morphine-induced impairment of memory acquisition is at least in part through the NO pathway. It is suggested that in short term spatial recognition memory, both inducible and constitutive NO synthases are involved, but in the long term fear memory, only the constitutive NO synthases indicated a prominent role in the anti-amnestic effect of pioglitazone on morphine-induced memory impairment.