National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing, 100191, China.
School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Sci Adv. 2023 Oct 27;9(43):eadi4462. doi: 10.1126/sciadv.adi4462. Epub 2023 Oct 25.
Energy supply, especially the transfer of lactate from astrocytes to neurons, is critical for neuronal plasticity. However, its role in the incubation of cocaine craving remains largely unknown. Using an extended-access self-administration model and in vivo H-magnetic resonance spectroscopy, we found that lactate synthesis in the central amygdala (CeA) is required for the intensified cocaine craving after prolonged withdrawal. Furthermore, incubated cocaine seeking was associated with a selective increase in monocarboxylate transporter 2 (MCT2) and MCT4 expression levels. Down-regulation of astrocytic MCT4 or neuronal MCT2 using targeted antisense oligonucleotides or cell type-specific shRNA attenuated cocaine craving and reduced the expression of plasticity-related proteins and excitatory synaptic transmission. Meanwhile, lactate administration rescued MCT4 but not MCT2 disruption-induced behavioral changes due to the inability of lactate to be transported into neurons. Together, our study highlights the critical role of astrocyte-neuron lactate transport in the CeA in the incubation of cocaine craving and suggests a potential therapeutic target for drug addiction.
能量供应，特别是将乳酸从星形胶质细胞转运到神经元，对神经元可塑性至关重要。然而，其在可卡因渴望潜伏期中的作用在很大程度上仍然未知。使用延长的自我给药模型和体内 H 磁共振波谱，我们发现中央杏仁核（CeA）中的乳酸合成对于长时间戒断后可卡因渴望的增强是必需的。此外，潜伏期可卡因寻求与单羧酸转运蛋白 2（MCT2）和 MCT4 表达水平的选择性增加有关。使用靶向反义寡核苷酸或细胞类型特异性 shRNA 下调星形胶质细胞 MCT4 或神经元 MCT2，可减弱可卡因渴望，并减少与可塑性相关的蛋白质和兴奋性突触传递的表达。同时，由于乳酸不能被转运到神经元中，乳酸的给药挽救了 MCT4 但没有挽救 MCT2 破坏诱导的行为变化。总之，本研究强调了 CeA 中星形胶质细胞-神经元乳酸转运在可卡因渴望潜伏期中的关键作用，并为药物成瘾提供了一个潜在的治疗靶点。
