Stress-induced neural activation is altered during early withdrawal from chronic methamphetamine

Chronic methamphetamine (MA) use can lead to increased symptoms of depression and anxiety during abstinence. Less is known about the specific brain regions that are altered following repeated MA that may be associated with these behavioral perturbations. Furthermore, MA has been reported to recruit and activate microglia in the brain, which may exacerbate stress-associated behavioral changes. In the present study, male and female mice were injected with MA (5 mg/kg) or saline once daily for 10 days, and during early withdrawal were assessed for alterations in immediate early gene (c-Fos) responses to a forced swim stressor. Chronic MA exposure increased floating and decreased swim time in the forced swim test in male and female mice tested 48 h after the final dose, indicating elevated depressive-like behavior. Furthermore, assessment of nest building, a measure of distress or despair-like behavior, revealed a sex-specific effect with only MA-treated females showing impairments. The c-Fos response to forced swim was attenuated by prior MA exposure in the central amygdala, CA3 hippocampal region, prefrontal cortex, and bed nucleus of the stria terminalis (BST). In the BST this attenuation occurred only in males. Neither the total number of microglia or activated microglia were altered by chronic MA exposure in regions examined. The primary findings indicate that chronic MA exposure attenuates activation of select stress-associated brain regions, a dysregulation that might contribute to alterations in mood-related behaviors.