Psychostimulant-induced neuroinflammation: the protective role of IL-10

Methamphetamine (Meth) is a powerful psychostimulant frequently studied as a model of exposure to psychoactive substances. It has been increasingly recognized for causing immunedysregulation and neuroinflammation associated to microglia and astrocyte reactivity. This neuroinflammation has been implicated in the initiation and maintenance of addiction. Recently, we have successfully demonstrated that microglia reactivity depends on astrocytic release of glutamate and TNFalfa after Meth exposure. Thus, interventions aimed at reducing inflammation may be useful in treating substance use disorders. Importantly, IL-10 is an anti-inflammatory cytokine that seems to counterbalance damage driven by excessive neuroinflammation, and can therefore be protective in several conditions.

Here, we took advantage of a transgenic mouse model with controlled overexpression of IL-10 to investigate the mechanisms of protection elicited by IL-10 in the context of acute exposure to Meth. Since IL-10 appears to act upon gammadelta (γΔ) T cells receptors, we are also using a transgenic mouse model with controlled overexpression of IL-10 but knock-out for γΔ T cells. To clearly determine the role of IL-10 overexpression for each cell population, namely microglia and astrocytes, we treated each cell population with Meth and increased doses of IL-10. We have already successfully shown that IL-10 overexpression prevents Meth-induced behaviors following a binge administration protocol. Importantly, this effect seems to be dependent on gammadelta (γΔ) T cells. Further, IL-10 also seems to be protective in Meth-induced microglia reactivity, marked by microglia proliferation and altered morphology. Our preliminary analysis showed that IL-10 increased levels in microglia could prevent these cells phagocytic activity, a hallmark of reactivity. This indicates a pivotal role of microglia cells under IL-10 overexpression. We predict that IL-10 will prove to be an innovative approach to devise treatment strategies for substance abuse disorders.