Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Japan.
Neurochem Res. 2022 Sep;47(9):2856-2864. doi: 10.1007/s11064-022-03680-3. Epub 2022 Jul 29.
Methamphetamine (METH), the most widely distributed psychostimulant, aberrantly activates the reward system in the brain to induce addictive behaviors. The presynaptic protein "Piccolo", encoded by Pclo, was identified as a METH-responsive protein with enhanced expression in the nucleus accumbens (NAc) in mice. Although the physiological and pathological significance of Piccolo has been identified in dopaminergic signaling, its role in METH-induced behavioral abnormalities and the underlying mechanisms remain unclear. To clarify such functions, mice with Piccolo knockdown in the NAc (NAc-miPiccolo mice) by local injection of an adeno-associated virus vector carrying miRNA targeting Pclo were generated and investigated. NAc-miPiccolo mice exhibited suppressed hyperlocomotion, sensitization, and conditioned place preference behavior induced by systemic administration of METH. The excessive release of dopamine in the NAc was reduced in NAc-miPiccolo mice at baseline and in response to METH. These results suggest that Piccolo in the NAc is involved in METH-induced behavioral alterations and is a candidate therapeutic target for the treatment of drug addiction.
甲基苯丙胺（METH）是分布最广泛的一种精神兴奋剂，它会异常激活大脑中的奖励系统，从而导致成瘾行为。突触前蛋白“Piccolo”，由 Pclo 编码，被鉴定为一种对 METH 有反应的蛋白质，在小鼠的伏隔核（NAc）中表达增强。尽管 Piccolo 在多巴胺能信号中的生理和病理意义已经得到确定，但它在 METH 诱导的行为异常中的作用及其潜在机制仍不清楚。为了阐明这些功能，通过局部注射携带靶向 Pclo 的 miRNA 的腺相关病毒载体，在 NAc 中敲低 Piccolo（NAc-miPiccolo 小鼠）生成并研究了这些小鼠。NAc-miPiccolo 小鼠表现出对系统给予 METH 诱导的过度运动、敏化和条件性位置偏好行为的抑制。在 NAc-miPiccolo 小鼠中，基线和对 METH 的反应中，NAc 中的多巴胺过度释放减少。这些结果表明，NAc 中的 Piccolo 参与了 METH 诱导的行为改变，是治疗药物成瘾的候选治疗靶点。
