SN79, a sigma receptor ligand, mitigates methamphetamine‐induced astrocyte and microglial activation

Abstract

Chronic methamphetamine (METH) exposure results in striatal neurotoxicity (reductions in monoamines and transporters) which can be prevented by sigma (σ) receptor antagonists. METH also activates astrocytes and microglia in the striatum, an effect implicated in its neurotoxic actions. σ receptors are expressed in glial cells and initial microarray analysis revealed σ receptor antagonist modulation of METH‐induced glial activation. The purpose of the current study was therefore, to determine if the putative σ receptor antagonist SN79 mitigates METH‐induced reactive gliosis and neuronal degeneration in the striatum. Male, Swiss Webster mice, quantitative real‐time PCR and immunohistochemistry were used to study striatal gene and protein expression changes related to astrocyte and microglial activation. METH treatment increased striatal gfap mRNA expression and morphologic activation of striatal astrocytes. METH also increased IBA‐1 and CD68 mRNA and protein expression, indicative of microglial activation. SN79 pretreatment attenuated METH‐induced activation of astrocytes and microglia in the striatum. Additionally, SN79 blocked METH‐induced neuronal degeneration as measured by Flouro‐Jade B staining. The current study demonstrates that σ receptor antagonism mitigates METH‐induced reactive gliosis and neuronal degeneration in the striatum. [Funding: DA013978, DA023205]