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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.

The effects of macerated extracts of Crocus sativus (Family Iridaceae) (saffron) on cell viability and cytokine release of stimulated peripheral blood mononuclear cells by phytohemagglutinin (PHA) and nonstimulated cells were examined. The effects of three concentrations of macerated extract, dexamethasone, and saline on cell viability and production of cytokines, including interleukin (IL)-4, IL-10, and interferon-γ (IFN-γ) were evaluated. In cells stimulated with PHA, different concentrations of the extract significantly inhibited cell viability of lymphocytes (P<.001 for all concentrations). High concentrations of the extract (500 μg/mL) also inhibited secretion of IFN-γ in stimulated cells and IL-10 secretion in both stimulated and nonstimulated cells (P<.05 for all cases). The effects of high and low concentrations of the extract (500 and 50 μg/mL, respectively) on IL-4 secretion were lower than that of dexamethasone (P<.05 to P<.001). The extract showed a stimulatory effect on IFN-γ and IL-4 secretion in nonstimulated cells. The ratios of IFN-γ to IL-4 in the presence of all concentrations of saffron on stimulated cells were significantly higher than for the control group (P<.05 to P<.01). These results indicated that the extract of saffron leads to increased ratio of IFN-γ to IL-4.

Neurocognitive impairment in response to methamphetamine (MA) has been proven in a variety of experimental and clinical studies. Elucidation of the underlying mechanisms of MA-induced cognitive deficits and finding preventive/therapeutic approaches need best-suited animal models. In modeling repeated MA exposure, while some believes that escalating doses simulate drug abuse conditions, others believe this regimen confers a preconditioning protection. The present study aimed to compare the effects of three different regimens of repeated MA administration on memory and cognitive function of adult rats. Rats in two different experimental groups were treated with escalating paradigms consisted of twice-daily i.p. injections; 1-4 mg/kg over 7 days or 1-10 mg/kg over 10 days. The third group received twice-daily doses of 15 mg/kg every other day over 14 days. Spatial working memory, novel object recognition task and anxiety-like behavior were measured sequentially in all MA-treated rats and vehicle-treated controls started from day 8 after last injection. All MA regimens decreased rates of spontaneous alternation in Y-maze and increased anxiety-like response. Short-term recognition memory was unchanged across all MA-treated animals, while long-term memory was impaired in the second and third MA regimen. Though MA deleterious effect especially in recognition memory is somehow dose dependent, preconditioning effect of increasing doses may be ruled out at least in the case of parameters measured here.

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