Leila Rezaeian - Department of Addiction Studies, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
Hamid Kalalian Moghadam - Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
Fahimeh Mohseni - Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
Mehdi Khaksari - Department of Physiology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
Raheleh Rafaiee - Department of Neuroscience, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran

Objective(s): This research aimed at evaluating the effect of berberine hydrochloride on anxiety-related behaviors induced by methamphetamine (METH) in rats, assessing relapse and neuroprotective effects. Materials and Methods: 27 male Wistar rats were randomly assigned into groups of Control, METH-withdrawal (METH addiction and subsequent withdrawal), and METH addiction with berberine hydrochloride oral treatment (100 mg/kg/per day) during the three weeks of withdrawal. Two groups received inhaled METH self-administration for two weeks (up to 10 mg/kg). The elevated plus maze (EPM) test and open field test (OFT) were carried out one day after the last berberine treatment and relapse was assessed by conditional place preference (CPP) test. TUNEL assay and immunofluorescence staining for NF-κB, TLR4, Sirt1, and α-actin expression in the hippocampus were tested. Results: After 3 weeks withdrawal, berberine hydrochloride decreased locomotor activity and reduced anxiety-related behaviors in comparison with the METH-withdrawal group (p <0.001). The obtained results from CPP showed that berberine significantly reduced relapse (p <0.01). Significantly decrease in activation of TLR4, Sirt1, and α-actin in METH-withdrawal group was found and the percentage of TLR4, Sirt1, and α-actin improved in berberine-treated group (p <0.001). A significant activity rise of NF-κB of cells in the METH-withdrawal group was detected compared to berberine-treated and control groups (p <0.001). Conclusion: Treatment with berberine hydrochloride via modulating neuroinflammation may be considered as a potential new medication for the treatment of METH addiction and relapse. The histological assays supported the neuroprotective effects of berberine in the hippocampus.

Anxiety, Berberine, Methamphetamine, Neuronal cell death, Neuroprotection, Relapse