Drug-induced activation of dopamine D1 receptor signaling and inhibition of class I/II histone deacetylase induce chromatin remodeling in reward circuitry and modulate cocaine-related Behaviors
Drug-induced activation of dopamine D1 receptor signaling and inhibition of class I/II histone deacetylase induce chromatin remodeling in reward circuitry and modulate cocaine-related Behaviors
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DOI：
10.1038/npp.2008.15
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发表时间：
2008-11-01
影响因子：
7.6
通讯作者：
Akbarian, Schahram
中科院分区：
文献类型：
--
作者：
Schroeder, Frederick A.;Penta, Krista L.;Akbarian, Schahram
染色质重塑，包括组蛋白修饰，参与兴奋剂诱导的基因表达和成瘾行为。为了进一步探索多巴胺D（1）受体信号传导的作用，我们测量了用D（1）激动剂SKF 82958和/或组蛋白去乙酰化酶抑制剂（HDACi）丁酸钠预处理长达10天的小鼠的可卡因相关运动活动和位置偏爱。与单一药物方案相比，D（1）激动剂和HDACi联合治疗显著增强可卡因诱导的运动活动和位置偏爱。然而，丁酸盐介导的奖赏效应是短暂的，仅在最后一次HDACi治疗后2天内明显。这些行为改变与纹状体和中脑腹侧的组蛋白修饰改变有关：（1）纹状体神经元H3磷酸乙酰化水平的普遍增加依赖于D（1）受体的激活;（2）中脑腹侧酪氨酸羟化酶（Th）和脑源性神经营养因子（Bdnf）启动子区H3脱乙酰化;以及用D1激动剂和HDACi共处理后相应基因转录物的上调。总的来说，这些发现意味着D（1）受体调节的组蛋白（磷酸化）乙酰化和基因表达的奖励电路是不同的调节区域特异性的方式。鉴于D（1）激动剂和HDACi的组合增强可卡因相关的致敏和奖励，D（1）受体拮抗剂和组蛋白乙酰转移酶抑制剂（HATi）的治疗益处需要在兴奋剂滥用的实验模型中进一步研究。
Chromatin remodeling, including histone modification, is involved in stimulant-induced gene expression and addiction behavior. To further explore the role of dopamine D(1) receptor signaling, we measured cocaine-related locomotor activity and place preference in mice pretreated for up to 10 days with the D(1) agonist SKF82958 and/or the histone deacetylase inhibitor (HDACi), sodium butyrate. Cotreatment with D(1) agonist and HDACi significantly enhanced cocaine-induced locomotor activity and place preference, in comparison to single-drug regimens. However, butyrate-mediated reward effects were transient and only apparent within 2 days after the last HDACi treatment. These behavioral changes were associated with histone modification changes in striatum and ventral midbrain: (1) a generalized increase in H3 phosphoacetylation in striatal neurons was dependent on activation of D(1) receptors; (2) H3 deacetylation at promoter sequences of tyrosine hydroxylase (Th) and brain-derived neurotrophic factor (Bdnf) in ventral midbrain, together with upregulation of the corresponding gene transcripts after cotreatment with D1 agonist and HDACi. Collectively, these findings imply that D(1) receptor-regulated histone (phospho) acetylation and gene expression in reward circuitry is differentially regulated in a region-specific manner. Given that the combination of D(1) agonist and HDACi enhances cocaine-related sensitization and reward, the therapeutic benefits of D(1) receptor antagonists and histone acetyl-transferase inhibitors (HATi) warrant further investigation in experimental models of stimulant abuse.