Possible Role of Cyclic AMP Response Element Binding/Brain-Derived Neurotrophic Factor Signaling Pathway in Mediating the Pharmacological Effects of Duloxetine against Methamphetamine Use-Induced Cognitive Impairment and Withdrawal-Induced Anxiety and Depression in Rats

Background: Duloxetine is used for treating depression and anxiety. The current study evaluated the effects of duloxetine against methamphetamine withdrawal-induced anxiety, depression, and motor disturbances and methamphetamine use-induced cognitive impairments. Materials and Methods: Ninety-six adult male rats were used for two independent experiments. Each experiment consisted of Groups 1 and 2 which received normal saline (0.2 ml/rat) and methamphetamine (10 mg/kg) respectively, Groups 3, 4, and 5 received both methamphetamine and duloxetine at doses of 5, 10, and 15 mg/kg, respectively. Groups 6, 7, and 8 received 5, 10, and 15 mg/kg of duloxetine, respectively. All administrations were performed for 21 days. In experiment 1, elevated plus maze (EPM), open-field test (OFT), forced swim test (FST), and tail suspension test (TST) were used to examine anxiety and depression in animals during withdrawal period. In experiment 2, Morris water maze (MWM) test was used to assess the effect of methamphetamine use followed by duloxetine treatment, on learning and memory. In the experiments, the expression of cyclic AMP response element binding (CREB) and brain-derived neurotrophic factor (BDNF) proteins were evaluated using enzyme-linked immunosorbent assay. Results: In the first experiment, duloxetine at all doses attenuated methamphetamine withdrawal induced-depression, anxiety, and motor disturbances in FST, OFT, EPM, and TST. In the second experiment, duloxetine at all doses attenuated methamphetamine use-induced cognitive impairment in MWM. In both experiments, duloxetine activated cAMP, CREB, and BDNF proteins' expression in methamphetamine-treated rats. Conclusions: Duloxetine can protect the brain against methamphetamine withdrawal-induced mood and motor disturbances and can also inhibit methamphetamine-induced cognitive impairment, possibly via cAMP/CREB/BDNF signaling pathway.