Department of Physiology, Binzhou Medical University, Shandong 264003, China; Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China.
Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2023 Jul 13;125:110758. doi: 10.1016/j.pnpbp.2023.110758. Epub 2023 Mar 25.
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.
甲基苯丙胺（METH）是一种高度成瘾的精神兴奋剂。脂肪细胞衍生的激素脂联素在大脑中有广泛的功能。然而，关于脂联素信号对 METH 诱导的条件位置偏好（CPP）的影响的研究有限，并且对潜在的神经机制知之甚少。使用 METH 诱导的成年雄性 C57/BL6J 小鼠模型来测试腹腔注射 AdipoRon（一种 AdipoR 激动剂）和罗格列酮（一种过氧化物酶体增殖物激活受体γ（PPARγ）选择性激动剂）、过表达海马齿状回（DG）中的脂联素受体 1（AdipoR1）以及化学遗传抑制 DG 的神经活性的治疗活性，还测量了神经发生因子、突触分子、谷氨酸受体和炎症细胞因子的变化。我们发现，METH 成瘾患者和小鼠的脂联素表达明显降低。我们的研究结果还表明，注射 AdipoRon 或罗格列酮可减轻 METH 诱导的 CPP 行为。此外，海马中的 AdipoR1 表达也减少了，AdipoR1 过表达通过对神经营养因子、突触分子和谷氨酸受体的调节作用阻断了 METH 诱导的 CPP 行为的发展。通过化学遗传方法观察到的海马齿状回（DG）的抑制性神经活性对 METH 诱导的 CPP 行为产生了治疗作用。最后，我们通过 PPARγ/脂联素/AdipoR1 轴鉴定了一些关键炎症细胞因子的异常表达。这项研究表明，脂联素信号是治疗 METH 成瘾的有前途的诊断和治疗靶点。
