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Long-term use of methamphetamine (MA) causes a broad range of cognitive deficits. Recently, it has been reported insulin signaling and mitochondrial biogenesis are involved in cognitive processes. This study aimed to examine whether MA induces cognitive deficits concomitant with insulin signaling impairment and mitochondrial dysfunctions and also intranasal (IN) insulin treatment can reverse cognitive deficits caused by MA. Rats were repeatedly treated with increasing doses of MA (1-10 mg/kg) twice a day for 10 days, and their cognitive functions were assessed using Y-maze, novel object recognition and passive avoidance tasks. The expression of components involved in insulin signaling (IR/IRS2/PI3K/Akt/GSK3β) and mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) was measured in the hippocampus. Therapeutic effects of IN insulin delivery (0.5- IU/day, for 7 days after MA discontinuation) were also investigated in MA-treated animals. Our results showed that repeated MA exposure induced cognitive deficits, and led to insulin signaling impairment and mitochondrial dysfunction. Interestingly, IN insulin treatment reduced MA-induced cognitive impairments possibly through activating insulin signaling, particularly PI3K/Akt/GSK3β pathway, and mitochondrial biogenesis. Thus, insulin and insulin signaling pathway can be considered as useful targets for the treatment of abnormalities associated with MA abuse., (© 2017 Wiley Periodicals, Inc.)