NMDA receptors interact with the retrieval memory enhancing effect of pioglitazone in mice.

Purpose: The present study has been undertaken to investigate the possible involvement of the glutamatergic pathway in the beneficial effects of pioglitazone on consolidation and retrieval phases of memory.

Materials And Methods: The Y-maze task was used to assess short-term spatial recognition memory in animals. Scopolamine (1mg/kg, i.p.) or MK-801 (dizocilpine) (0.03, 0.1 and 0.3mg/kg, i.p.) were administered immediately after the training session to impair memory consolidation or 30min before the retention trial to impair memory retrieval. Pioglitazone (10, 20, 40 and 80mg/kg, p.o.) was administered 2h before the retention session in memory retrieval experiments or immediately after the training session in consolidation experiments. And finally NMDA (N-methyl-d-aspartate) (75mg/kg, i.p) was administered 15min before the administration of pioglitazone.

Results: 1) MK-801 (0.3mg/kg) impaired the retrieval of spatial recognition memory. 2) Pioglitazone failed to improve MK-801 induced impairment of retrieval of spatial recognition memory. 3) The 20mg/kg dose of pioglitazone significantly improved memory in mice with scopolamine induced impairment of memory retrieval. 4) Sub-effective dose of MK-801 (0.1mg/kg) was capable of reversing the beneficial effect of pioglitazone on retrieval of memory in scopolamine-treated mice, 5) Administration of NMDA (75mg/kg) and a sub-effective dose of pioglitazone (10mg/kg) reversed the effect of scopolamine and promoted memory retrieval. 6) MK-801 did not affect the consolidation phase of spatial recognition memory. 7) Pioglitazone did not affect scopolamine-induced impairment of memory consolidation.

Conclusions: Sub-effective dose of MK-801 is capable of reversing the protective action of pioglitazone on scopolamine-induced impairment of memory retrieval. Additionally, co-administration of 75mg/kg NMDA and a sub-effective dose of pioglitazone potentiated the effect of pioglitazone on memory retrieval impaired by scopolamine. These results support the idea that pioglitazone plays its memory retrieval enhancement role through the glutamatergic pathway.