Abstinence from repeated amphetamine treatment induces depressive-like behaviors and oxidative damage in rat brain

Amphetamine has a significant potential for abuse and addiction. Among prolonged abusers, amphetamine withdrawal-induced depressive symptoms are common; however, their pathophysiological mechanism is not fully understood. Previously, we found that repeated treatment with amphetamine for 2 weeks induced oxidative stress in rat brain. The purpose of the current study is to analyze whether abstinence from repeated amphetamine treatment in rats induces depressive-like behaviors and if oxidative damage in the brain continues during abstinence. Rats were given repeated treatment with amphetamine once daily at 1, 2, or 4 mg/kg for 14 days. From 10 to 14 days after final amphetamine treatment, behavioral changes were monitored using open field test, novel object recognition test, and forced swim test. Oxidative damage in the medial frontal cortex and hippocampus was analyzed by immunohistochemistry. We found that drug abstinence after repeated amphetamine stimulation decreased locomotor activity and exploratory behavior in the open field test, increased immobility in the forced swim test, and had no significant effect on the recognition index in the novel object recognition test. We also found that amphetamine abstinence increased levels of 4-hydroxynonenal-protein adducts and 8-hydroxyguanosine in rat medial frontal cortex and in CA3 and dentate gyrus regions of the hippocampus. These results suggest that amphetamine abstinence displays depressive-like behaviors in rats and induces oxidative damage to lipids and RNA in rat brain. Our findings indicate that the process of oxidative stress may play a role in pathophysiological changes during drug abstinence from repeated amphetamine stimulation.