Department of Pharmacology and Toxicology, Program in Neuroscience, Research Institute on Addictions, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Department of Physiology and Biophysics, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Nat Commun. 2019 Sep 12;10(1):4140. doi: 10.1038/s41467-019-12122-8.
Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1 subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.
伏隔核(NAc)和其他大脑奖励区域中的持续转录和形态事件导致了药物成瘾的特征性持久行为适应。阿片类药物暴露会减少 NAc 中中等棘突神经元的树突棘密度;然而,介导这种现象的潜在转录和细胞事件尚不清楚。我们发现海洛因自我给药会负调控 NAc 中的肌动蛋白结合蛋白 drebrin。通过病毒介导的基因转移,我们发现 NAc 中的 drebrin 过表达足以减少药物寻求行为并增加树突棘密度,而 drebrin 敲低则增强了这些效应。我们证明 drebrin 受到组蛋白修饰酶 HDAC2 的转录抑制,组蛋白去乙酰化酶的药理学抑制可缓解这种抑制。重要的是,我们证明海洛因诱导的适应仅发生在中等棘突神经元的 D1 亚群中。这些发现确立了 drebrin 和上游转录调节剂 HDAC2 在 NAc 中阿片类药物诱导的可塑性中的重要作用。