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Chronic use of methamphetamine (MA), a neurotoxic psychostimulant, leads to long-lasting cognitive dysfunctions in humans and animal models. Thyroid hormones (THs) have several physiological actions and are crucial for normal behavioral, intellectual and neurological development. Considering the importance of THs in the cognitive processes, the present study was designed to evaluate the therapeutic effects of THs on cognitive and neurological impairments induced by MA. Escalating doses of MA (1-10 mg/kg, IP) were injected twice daily for 10 consecutive days in rats and cognitive functions were evaluated using behavioral tests. The expression of factors involved in neurogenesis (NES and DCX), mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM), neuroinflammation (GFAP, Iba-1, and COX-2) as well as Reelin and NT-3 (synaptic plasticity and neurotrophic factor, respectively) was measured in the hippocampus of MA-treated animals. The effects of three different doses of T4 (20, 40 or 80 μg/kg; intraperitoneally) or T3 (20, 40 or 80 μg/rat; 2.5 μl/nostril; intranasal) treatment, once a day for one week after MA cessation, were assessed in MA-treated rats. After the last behavioral test, serum T4 and T3 levels were measured using radioimmunoassay. The results revealed that repeated escalating regimen of MA impaired cognitive functions concomitant with neurogenesis and synaptic plasticity impairments, mitochondrial dysfunction, and neuroinflammation. T4 or T3 treatment partially decreased the alterations induced by MA. These findings suggest that THs can be considered as potential candidates for the reduction of MA abuse related neurocognitive disturbances., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.