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

Abstract

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.

Gut microbiota from sigma-1 receptor knockout mice induces depression-like behaviors and modulates the cAMP/CREB/BDNF signaling pathway

“…Brain-derived neurotrophic factor is a direct target of CREB ( Barco et al, 2005 ), and cAMP-activated phosphorylated CREB regulates the expression of neurotrophic factors such as BDNF and NGF ( Ortega-Martinez, 2015 ). The cAMP/CREB/BDNF pathway has been shown to be an important mechanism of action in traditional Chinese medicine ( Cai et al, 2022 ) and novel antidepressants such as vortioxetine ( Ramezany et al, 2019 ). In the hippocampal mRNA sequencing of Sig-1R knockout mice, the cAMP signaling pathway was significantly enriched.…”

GLP-1 plays a protective role in hippocampal neuronal cells by activating cAMP-CREB-BDNF signaling pathway against CORT+HG-induced toxicity

“…In the chronic unpredictable stress animal model, CREB expression was inhibited in the hippocampal CA1 region; however, CREB levels recovered after antidepressant treatment [ 33 ]. Through modulation of cAMP-CREB-BDNF and other similar signaling pathways, numerous neuroprotective agents have been developed against neurodegenerative and neurobehavioral disorders [ 34 ]. This study observed that the PKA, p -CREB, and p -Trkb (BDNF-specific receptor) expressions were significantly increased after the GLP-1 treatment to the culture medium of HT22 cells, which were damaged by CORT + HG, suggesting that GLP-1 could up-regulate the cAMP-CREB-BDNF signaling pathway.…”

How Antidepressant Drugs Affect the Antielectroshock Action of Antiseizure Drugs in Mice: A Critical Review

“…Fluoxetine increased the hypothalamic BDNF expression in mice [ 52 ], while milnacipran enhanced BDNF protein and mRNA levels in the mouse cerebral cortex [ 53 ]. On the other hand, duloxetine activated the BDNF protein expression in brains of rats subjected to the methamphetamine model of anxiety [ 54 ]. Desipramine, fluoxetine, and tianeptine increased the BDNF mRNA and protein expression in stressed rats [ 55 ].…”