Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
Mol Psychiatry. 2018 Mar;23(3):629-638. doi: 10.1038/mp.2017.46. Epub 2017 Mar 28.
Adult neurogenesis in the dentate gyrus (DG) is strongly influenced by drug-taking behavior and may have a role in the etiology of drug-seeking behavior. However, mechanistic studies on the relationship of neurogenesis on drug seeking are limited. Outbred Wistar rats experienced extended access methamphetamine self-administration and individual differences in drug taking defined animals with higher preferred and lower preferred levels of drug intake. Forced abstinence from higher preferred levels of drug taking enhanced neurogenesis and neuronal activation of granule cell neurons (GCNs) in the DG and produced compulsive-like drug reinstatement. Systemic treatment with the drug Isoxazole-9 (a synthetic small molecule known to modulate neurogenesis in the adult rodent brain) during abstinence blocked compulsive-like context-driven methamphetamine reinstatement. Isoxazole-9 modulated neurogenesis, neuronal activation and structural plasticity of GCNs, and expression of synaptic proteins associated with learning and memory in the DG. These findings identify a subset of newly born GCNs within the DG that could directly contribute to drug-seeking behavior. Taken together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement.
成年海马齿状回（DG）中的神经发生强烈受到药物使用行为的影响，并且可能在觅药行为的发病机制中起作用。然而，关于神经发生与觅药关系的机制研究有限。杂种 Wistar 大鼠经历了延长的甲基苯丙胺自我给药，并且药物摄入的个体差异定义了具有更高和更低偏好水平药物摄入的动物。从更高偏好水平的药物摄入中强制禁欲增强了 DG 中的神经发生和颗粒细胞神经元（GCN）的神经元激活，并产生了强迫性药物再摄取。在禁欲期间，全身性给予异恶唑-9（一种已知在成年啮齿动物大脑中调节神经发生的合成小分子）治疗阻断了强迫性情境驱动的甲基苯丙胺再摄取。异恶唑-9 调节了 DG 中 GCN 的神经发生、神经元激活和结构可塑性，以及与学习和记忆相关的突触蛋白的表达。这些发现确定了 DG 内的一组新的 GCN，它们可能直接有助于觅药行为。综上所述，这些结果支持了在强迫性药物再摄取中，成年神经发生在禁欲期间的直接作用的重要性。
