未经证实:重复服用可卡因会改变伏隔核(NAc)内Lys残基和脱氧核糖核酸(DNA)的组蛋白乙酰化和甲基化。最近,雀巢的研究小组探索了奖励处理模型中的组蛋白Arg(R)甲基化。Damez-Werno等人.(2016)报告说,在人类调查和动物自我管理实验中,在啮齿动物和可卡因依赖型人NAc中,组蛋白标记蛋白-R-甲基转移酶-6(PRMT6)和组蛋白H3(H3R2me2a)上R2的不对称二甲基化降低。在所有NAc神经元的D2-MSNs中PRMT6的过表达增加了可卡因的寻找,而D1-MSN中的PRMT6过表达可防止可卡因寻求。
UNASSIGNED:假设是在精神兴奋剂使用障碍(PSU)中发生多巴胺化(H3R2me2a结合),和结合抑制剂Srcin1,如主要的DRD2A2等位基因多态性,通过使伏隔核(NAc)多巴胺表达正常化来防止精神兴奋剂寻求行为。
UNASSIGNED:许多出版物证实了DRD2TaqA1等位基因(D2受体数量降低30-40)与严重可卡因依赖之间的关联。Lepack等人。(2020)发现急性可卡因会增加NAc突触中的多巴胺,并导致组蛋白H3谷氨酰胺5的多巴胺化(H3Q5dop)和随后的D2表达抑制。抑制随着长期使用可卡因和可卡因戒断而增加。他们还发现,在可卡因戒断期间,Src激酶信号传导抑制剂1(Srcin1或p140CAP)降低了H3R2me2a的结合。因此,这种抑制的多巴胺化诱导了“稳态制动”。\"
未经证实:NAcD2-MSN中Src信号的减少,(像DRD2TaqA2等位基因一样,一种众所周知的抗SUD的遗传机制)使NAc多巴胺表达正常化,并降低可卡因奖励和自我施用可卡因的动机。Srcin1可能是一个重要的治疗靶点。
UNASSIGNED: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler\'s group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during human investigations and animal self-administration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking.
UNASSIGNED: The hypothesis is that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression.
UNASSIGNED: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, and results in histone H3 glutamine 5 dopaminylation (H3Q5dop) and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase signaling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a \"homeostatic brake.\"
UNASSIGNED: The decrease in Src signaling in NAc D2-MSNs, (like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD) normalizes the NAc dopamine expression and decreases cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.