Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus.
Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus.
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DOI：
10.1038/npp.2009.66
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发表时间：
2009-10
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影响因子：
--
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中科院分区：
文献类型：
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抑制磷酸二酯酶-4（PDE 4）（一种催化环腺苷酸（cAMP）水解的酶），增加cAMP反应元件结合蛋白（pCREB）的磷酸化和海马神经发生，并对行为产生抗抑郁样作用;然而，尚未建立这些之间的因果关系。在本研究中，长期服用咯利普兰对小鼠的行为产生抗抑郁和抗焦虑样作用。它还增加了海马和前额皮质的cAMP和pCREB水平，但增加了Sox 2，一种有丝分裂祖细胞的标志物，只在海马中。慢性咯利普兰治疗也增加海马神经发生，证明了增加溴脱氧尿苷（BrdU）阳性细胞在海马齿状回。甲基偶氮氧甲醇（MAM），这是有毒的增殖细胞，逆转咯利普兰诱导的增加BrdU阳性细胞和pCREB在海马和部分阻断其行为的影响。大约84%的BrdU阳性细胞成为新生神经元，其中93%共表达pCREB，这些比例没有改变咯利普兰或MAM，无论是单独或组合。最后，在MAM治疗结束后三周，当神经发生不再被抑制时，咯利普兰再次增加海马pCREB，其抗抑郁和抗焦虑样作用恢复。总体而言，目前的结果表明，咯利普兰产生的方式，至少部分取决于其在海马体中的神经原性作用的行为的影响，靶向有丝分裂祖细胞，而不是新生或成熟的神经元;海马新生神经元的cAMP/CREB信号是神经发生的关键，并有助于行为的咯利普兰的影响。
Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of cAMP-response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these have not been established. In the present study, chronic administration of rolipram produced antidepressant- and anxiolytic-like effects on behavior in mice. It also increased cAMP and pCREB levels in the hippocampus and prefrontal cortex, but increased Sox2, a marker for mitotic progenitor cells, only in the hippocampus. Chronic rolipram treatment also increased hippocampal neurogenesis, as evidenced by increased bromodeoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus. Methylazoxymethanol (MAM), which is toxic to proliferating cells, reversed rolipram-induced increases in BrdU-positive cells and pCREB in the hippocampus and partially blocked its behavioral effects. Approximately 84% of BrdU-positive cells became newborn neurons, 93% of which co-expressed pCREB; these proportions were not altered by rolipram or MAM, either alone or in combination. Finally, three weeks following the end of MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB, with its antidepressant- and anxiolytic-like effects resumed. Overall, the present results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram.
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影响因子：
2.7
作者：
Bani-Yaghoub, Mahmud;Tremblay, Roger G.;Sikorska, Marianna
通讯作者：
Sikorska, Marianna
DOI：
10.1016/s0167-4781(01)00164-6
发表时间：
2001-03-19
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Cherry, JA;Thompson, BE;Pho, V
通讯作者：
Pho, V
DOI：
10.1073/pnas.120552597
发表时间：
2000-06-20
影响因子：
11.1
作者：
Eisch, AJ;Barrot, M;Nestler, EJ
通讯作者：
Nestler, EJ
DOI：
10.1073/pnas.0601992103
发表时间：
2006-05-23
影响因子：
11.1
作者：
Encinas, Juan M.;Vaahtokari, Anne;Enikolopov, Grigori
通讯作者：
Enikolopov, Grigori
DOI：
10.1073/pnas.95.25.15020
发表时间：
1998-12-08
影响因子：
11.1
作者：
Barad, M;Bourtchouladze, R;Kandel, E
通讯作者：
Kandel, E