Blocking IL-17A inhibits methamphetamine-induced hyperlocomotion and conditioned place preference and prevents methamphetamine abstinence-induced depression-like behaviors in mice.

We demonstrated previously that blocking IL-17A, a proinflammatory cytokine, prevents oxycodone-induced depression-like effects and anxiety-like effects during abstinence from MDPV (a psychostimulant) in rats. Here, we tested the hypothesis that eliminating IL-17A signaling (pharmacological antagonism using IL-17A Ab or genetic deletion of IL-17RC) would inhibit behavioral and neurochemical effects elicited by methamphetamine (METH) exposure and abstinence in adult mice. We investigated rewarding and locomotor-activating effects of METH and withdrawal-induced anxiety- and depression-like effects during METH abstinence. Mice received saline or METH (5 mg/kg, IP) once daily for 18 d. Locomotion was measured on days 1 and 15. Anxiety- and depression-like effects were investigated 72 and 96 h after the last METH injection using the elevated plus maze and forced swim test, respectively. IL-17A antibody (Ab, 60 μg/100 μl, IP) was injected every 3rd day of METH exposure. METH-induced hyperlocomotion was significantly reduced in IL-17RC knockout mice or by treatment with the IL-17A Ab (100 μg/100 μl). Neutralization of IL-17A or genetic deletion of IL-17RC prevented development of depression-like effects during METH abstinence. Also, mRNA levels of IL-17RC, but not IL-17RA, in the NAC were enhanced during METH abstinence. Development of METH conditioned place preference (CPP) was prevented by IL-17A Ab but was not affected by IL-17RC deletion in mice conditioned with METH (3 mg/kg) for 4 d. Our data show that abolishing IL-17A signaling reduces METH-induced hyperlocomotion and CPP and attenuates depression-like effects during METH abstinence. These results highlight studying IL-17A blockade as a neuroimmune-based approach to mitigate METH adverse effects.