Methamphetamine causes persistent immune dysregulation: a cross-species, translational report

Abstract

Methamphetamine (MA) dependence causes serious cognitive impairments that can persist during abstinence and negatively affect recovery outcomes. Evidence suggests that immune factors, such as cytokines, chemokines, and cellular adhesion molecules, contribute to MA-induced immune dysfunction, neuronal injury, and persistent cognitive impairments, yet the role of MA-induced brain inflammation remains unclear. To address this question, we used a cross-species, translational approach. Thirty-two male C57BL/6J mice were administered MA (1 mg/kg) or saline subcutaneously for seven consecutive days. Mice were euthanized at 72 h or 3 weeks after the last drug dose, and blood and brain samples were collected. In addition, 20 adults in remission from MA dependence and 20 non-dependent controls completed neuropsychological assessments and a blood draw. Multiplex assays were used to measure cytokine, chemokine, and intercellular adhesion molecule (ICAM-1) expression in mouse and human samples. A number of significant MA-induced changes in neuroimmune factors were observed. Of particular interest were the chemokine monocyte chemoattractant protein 1 (MCP-1) and the cellular adhesion molecule ICAM-1, which were similarly increased in the plasma of MA exposed mice as well as humans. In human participants, MA-induced changes in the cytokine and chemokine milieu were accompanied by increased cognitive impairments. Mice showing MA-induced changes in peripheral immune molecule expression also had significant brain-region specific changes in pro-inflammatory cytokines, chemokines, and ICAM-1. This cross-species, translational study suggests that chronic CNS immune dysregulation may in part contribute to the longlasting neuropsychiatric consequences of MA dependence.

Fig. 1

Seventy-two hours and 3 weeks following drug administration, neuroimmune factors were significantly altered in the frontal cortex, neostriatum and hippocampus of MA- as compared to SAL-treated mice. Mixed-effects models were used to estimate treatment effects of MA over time and in different brain regions. Significant treatment effects of MA were found for IL-1β (P = 0.045) and MCP-1 (P = 0.035) in the frontal cortex (a, b), for IL-2 (P = 0.009) in the neostriatum (c), and for IL-1β (P = 0.018) (d), IL-2 (P = 0.001) (e), IL-6 (P = 0.007) (f), MIP-1β (P = 0.021) (g), MIP-1α (P = 0.025) (h) and ICAM-1 (P = 0.000) (i) in the hippocampus at 72 h following the last drug dose. Panels j–l show the cytokines that were significantly changed in MA-LR as compared to SAL-LR groups [IL-1β (P = 0.020), IL-10 (P = 0.002) and IFN-α (P = 0.003). * Denotes two-sided P-values less than 0.05