Hippocampal Serotonin and Responses to Immobilization Stress in Rats Treated with Metformin

Abstract

Background: Stress-related illnesses and depression are rising in modern society. Selective serotonin reuptake inhibitors as well as other antidepressants, are also not very effective and commonly exhibit partial remission, suggesting the need for novel therapeutic agents for treating anxiety and depression. Objective: The present study was designed to investigate serotonergic mechanisms in the potential anxiolytic and stress-reducing effects of metformin. Method: In the first experiment, rats were given two doses (50 and 100mg/kg) of metformin to monitor the effects of repeated administration on motor activity, anxiety, and 5-HT-1A receptor expression in the hippocampus and raphe nuclei. The second experiment was conducted in 2 parts, in 2a. experiment, control, and metformin (50 mg/kg) treated rats were immobilized for 2 hours for 5 consecutive days. Food intake and body weight were monitored daily and anxiety-like behavior was monitored on days 2 and 6. On day 6, rats were again immobilized for 2 hours, and after termination of stress rats were sacrificed to collect the hippocampus for HPLC-EC analysis of serotonin (5-hydroxytryptamine; 5-HT) and 5-hydroxy indole acetic acid (5-HIAA). In 2b. experiment, control, and metformin (50 mg/kg) treated rats were immobilized for 2 hours, and after 2 hours rats were sacrificed to collect the hippocampus for HPLC-EC analysis of 5-HT and 5-HIAA. Results: We found that metformin treatment exhibited anxiety reduction associated with greater expression of 5-HT-1A receptor in the hippocampus and reduced expression in the raphe nuclei. Immobilization stress-induced food intake and body weight deficits were comparable in control and metformin-treated rats, but the anxiogenic effects of stress were smaller in the metformintreated group. Stress-induced decreases of hippocampal 5-HT were smaller in metformin-treated than in control rats. result: We found that metformin treatment exhibited anxiety reduction associated with greater expression of 5-HT-1A receptor in the hippocampus and reduced expression in the raphe. Immobilization stress-induced food intake and body weight deficits were comparable in control and metformin-treated rats, but the anxiogenic effects of stress were smaller in the metformin-treated group. Stress-induced decreases of hippocampal 5-HT were smaller in metformin-treated than in control rats. Conclusion: Metformin can reduce stress-induced anxiety mediated via an increase in hippocampal 5-HT levels and 5-HT-1A heteroreceptor expression.