Chronic exposure to corticosterone enhances the neuroinflammatory and neurotoxic responses to methamphetamine

J. Neurochem. (2012) 122, 995–1009. Up‐regulation of proinflammatory cytokines and chemokines in brain (“neuroinflammation”) accompanies neurological disease and neurotoxicity. Previously, we documented a striatal neuroinflammatory response to acute administration of a neurotoxic dose of methamphetamine (METH), i.e. one associated with evidence of dopaminergic terminal damage and activation of microglia and astroglia. When we used minocycline to suppress METH‐induced neuroinflammation, indices of dopaminergic neurotoxicity were not affected, but suppression of neuroinflammation was incomplete. Here, we administered the classic anti‐inflammatory glucocorticoid, corticosterone (CORT), in an attempt to completely suppress METH‐related neuroinflammation. METH alone caused large increases in striatal proinflammatory cytokine/chemokine mRNA and subsequent astrocytic hypertrophy, microglial activation, and dopaminergic nerve terminal damage. Pre‐treatment of mice with acute CORT failed to prevent neuroinflammatory responses to METH. Surprisingly, when mice were pre‐treated with chronic CORT in the drinking water, an enhanced striatal neuroinflammatory response to METH was observed, an effect that was accompanied by enhanced METH‐induced astrogliosis and dopaminergic neurotoxicity. Chronic CORT pre‐treatment also sensitized frontal cortex and hippocampus to mount a neuroinflammatory response to METH. Because the levels of chronic CORT used are associated with high physiological stress, our data suggest that chronic CORT therapy or sustained physiological stress may sensitize the neuroinflammatory and neurotoxicity responses to METH. Amphetamines, brain inflammation and neurotoxicity … stress may make a bad situation worseSystemic methamphetamine (METH) exposure causes large increases in striatal proinflammatory cytokines/chemokines and subsequent astrocytic hypertrophy, microglial activation, and dopaminergic nerve terminal damage. In an effort to evaluate the potential role of neuroinflammation in this neurotoxicity, we attempted to suppress the inflammation with the classic anti‐inflammatory glucocorticoid, corticosterone (CORT). Surprisingly, when pre‐treated with chronic CORT, an enhanced striatal neuroinflammatory response to METH was observed, an effect that was accompanied by enhanced METH‐induced gliosis and dopaminergic neurotoxicity. Chronic CORT pre‐treatment also sensitized the frontal cortex and hippocampus to mount a neuroinflammatory response to ME