PPARγ/Adiponectin axis attenuates methamphetamine-induced conditional place preference via the hippocampal AdipoR1 signaling pathway.

Methamphetamine (METH) is a highly addictive psychostimulant. The adipocyte-derived hormone adiponectin has a broad spectrum of functions in the brain. However, limited research has been conducted on the effect of adiponectin signaling on METH-induced conditioned place preference (CPP) and knowledge of the underlying neural mechanisms is scarce. The METH induced adult male C57/BL6J mice model were used for testing the therapeutic activities of intraperitoneal injection of AdipoR agonist AdipoRon and peroxisome proliferator-activated receptor gamma (PPARγ)-selective agonist rosiglitazone, adiponectin receptor 1 (AdipoR1) overexpression in hippocampal dentate gyrus (DG), and chemogenetic inhibiting the neural activity of DG, and the changes of neurotrophic factors, synaptic molecules, glutamate receptors, and inflammatory cytokines were also measured. We found that adiponectin expression was significantly reduced in METH addicted patients and mice. Our findings also showed that injection of AdipoRon or rosiglitazone alleviated the METH-induced CPP behavior. Moreover, the expression of AdipoR1 in the hippocampus was also reduced, and AdipoR1 overexpression blocked the development of METH-induced CPP behavior through regulatory effects on neurotrophic factors, synaptic molecules, and glutamate receptors. The observed inhibitory neural activity of the hippocampal dentate gyrus (DG) induced via a chemogenetic approach produced a therapeutic effect on the METH-induced CPP behavior. Finally, we identified an abnormal expression of some key inflammatory cytokines through the PPARγ/Adiponectin/AdipoR1 axis. This study demonstrates that adiponectin signaling is a promising diagnostic and therapeutic target for METH addiction.