Laboratoire de Neurosciences Cognitives et Adaptatives, Université de Strasbourg, Strasbourg, France.
Int J Neuropsychopharmacol. 2013 Aug;16(7):1587-97. doi: 10.1017/S1461145712001630. Epub 2013 Feb 4.
The C-type natriuretic peptide (CNP) exerts its action via stimulation of the cyclic GMP (cGMP) signalling pathway, which includes the activation of cGMP-dependent protein kinases. The pathway can also be activated by inhibitors of phosphodiesterases (PDE) that hydrolyse cGMP. The present report shows that activation of the cGMP pathway by CNP, by bromo-cGMP, a cell-permeant cGMP analogue, or by the PDE inhibitor zaprinast dose dependently reduces intravenous cocaine self-administration by rats. The effect was found when the compounds were injected in situ into the prefrontal cortex, but not when they were injected into the nucleus accumbens. A decrease in the number of cocaine infusions performed by rats was obtained under the fixed ratio-1 schedule of reinforcement as well as under a progressive ratio schedule, which evaluates the motivation of the animals for the drug. Decrease in cocaine self-administration was accompanied with reduced expression of the epigenetic markers methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2) in dopaminergic projection areas. An increase in the acetylation level of histone H3, but not of histone H4, was also noticed. Since MeCP2 and HDAC2 are known to modulate dynamic functions in the adult brain, such as synaptic plasticity, our results showing that activation of the cGMP signal transduction pathway decreased both cocaine intake and expression of the epigenetic markers strongly suggest that the MeCP2/HDAC2 complex is involved in the analysis of the reinforcing properties of cocaine in the prefrontal cortex.
C 型利钠肽（CNP）通过刺激环鸟苷酸（cGMP）信号通路发挥作用，该通路包括 cGMP 依赖性蛋白激酶的激活。该通路也可被磷酸二酯酶（PDE）抑制剂激活，这些抑制剂可水解 cGMP。本报告显示，CNP、细胞通透型 cGMP 类似物溴代-cGMP 或 PDE 抑制剂扎普司特激活 cGMP 通路可剂量依赖性地减少大鼠静脉内可卡因的自我给药。当化合物原位注射到前额叶皮质时，会发现这种效应，但当它们注射到伏隔核时则不会。在固定比率-1强化方案以及评估动物对药物动机的递增比率方案下，都观察到了大鼠可卡因注射次数的减少。可卡因自我给药的减少伴随着多巴胺能投射区中表观遗传标记物甲基-CpG 结合蛋白 2（MeCP2）和组蛋白去乙酰化酶 2（HDAC2）表达的减少。还注意到组蛋白 H3 的乙酰化水平增加，而组蛋白 H4 的乙酰化水平没有增加。由于 MeCP2 和 HDAC2 已知可调节成年大脑中的动态功能，如突触可塑性，我们的结果表明，cGMP 信号转导通路的激活不仅减少了可卡因的摄入，还减少了表观遗传标记物的表达，这强烈表明 MeCP2/HDAC2 复合物参与了前额叶皮质中可卡因强化特性的分析。
