目的:观察褪黑素(melatonin,Mel)对大鼠吗啡诱导的条件性位置偏爱(CPP)效应表达的影响及此过程中脑内cAMP反应元件结合蛋白(CREB)及其磷酸化的变化。方法:(1)大鼠连续6 d给予吗啡(sc,5 mg.kg-1/d)建立CPP模型,于CPP测试前20 min ip Mel...目的:观察褪黑素(melatonin,Mel)对大鼠吗啡诱导的条件性位置偏爱(CPP)效应表达的影响及此过程中脑内cAMP反应元件结合蛋白(CREB)及其磷酸化的变化。方法:(1)大鼠连续6 d给予吗啡(sc,5 mg.kg-1/d)建立CPP模型,于CPP测试前20 min ip Mel(50和25 mg.kg-1),观察Mel对大鼠吗啡诱导的CPP效应表达的影响。(2)大鼠同上建立吗啡CPP模型,d7上、下午,d8上午ip Mel 50 mg.kg-1,共3次,最后一次ip后6 h,采用免疫组化结合计算机图像处理技术测定脑内伏隔核、海马内CREB及磷酸化CREB(p-CREB)的免疫阳性反应强度。结果:Mel 50 mg.kg-1可显著翻转大鼠吗啡诱导的CPP评分升高(P<0.01),同时显著降低吗啡诱导的大鼠伏隔核、海马内p-CREB的上调(P<0.01)。结论:Mel抑制大鼠吗啡奖赏效应的表达,此作用可能与其抑制吗啡诱导的伏隔核、海马内p-CREB蛋白水平上调有关。展开更多
PDE is a supeffamily of enzymes that break down the important second messengers cyclic AMP （cAMP） PDE4 is the most important fami- and cyclic GMP （cGMP）. There are 11 PDE families （ PDEI-11 ） ; among them, ly i...PDE is a supeffamily of enzymes that break down the important second messengers cyclic AMP （cAMP） PDE4 is the most important fami- and cyclic GMP （cGMP）. There are 11 PDE families （ PDEI-11 ） ; among them, ly in the control of intracellular cAMP signaling. It has been established that PDE4 is an essential player in the me- diation of AD and alcoholism. Chronic alcohol consumption can cause alcohol-related dementia and 50% - 75% of detoxified alcoholics have memory or cognition impairment. The lecture will focus on the unique role of PDE4 and its isoforms （PDE4A-D） in mediating AD and alcoholism and the cellular mechanisms involved. Specifically, using mice deficient in PDE4A, PDE4B, or PDE4D, and their wild type （WT） controls, it was found that PDE4Adeficiencydecreased alcohol intake and preference and reversed Abeta42-induced memory deficits. In con- trast, deficiency of PDE4B only mimicked the ability of PDE4A-deficiency to reduce alcohol consumption, while deficiency of PDE4D only reversed Abeta42-induced memory deficits. In addition, levels of cAMP and phospho- CREB （pCREB） were increased in the hippocampus of mice deficient in PDE4A or PDE4D, which also produced reversal of Abeta42-induced decreases in pCREB. These datasuggest that PDE4 isoforms have different roles in me-diating alcohol-drinking behavior and memoryin Alzheimer＇ s disease, which are mediated by cAMP/CREB signa- ling. The results indicate PDE4A as a potential new target for alcohol-related dementia, although studies with ani- mal models of alcohol-related dementia are needed to clarify this.展开更多
基金supported by grants from The National Key Research and Development Program of China(2017YFA0504000)The National Natural Science Foundation of China(31570857,91849203,31800969)~~
文摘PDE is a supeffamily of enzymes that break down the important second messengers cyclic AMP （cAMP） PDE4 is the most important fami- and cyclic GMP （cGMP）. There are 11 PDE families （ PDEI-11 ） ; among them, ly in the control of intracellular cAMP signaling. It has been established that PDE4 is an essential player in the me- diation of AD and alcoholism. Chronic alcohol consumption can cause alcohol-related dementia and 50% - 75% of detoxified alcoholics have memory or cognition impairment. The lecture will focus on the unique role of PDE4 and its isoforms （PDE4A-D） in mediating AD and alcoholism and the cellular mechanisms involved. Specifically, using mice deficient in PDE4A, PDE4B, or PDE4D, and their wild type （WT） controls, it was found that PDE4Adeficiencydecreased alcohol intake and preference and reversed Abeta42-induced memory deficits. In con- trast, deficiency of PDE4B only mimicked the ability of PDE4A-deficiency to reduce alcohol consumption, while deficiency of PDE4D only reversed Abeta42-induced memory deficits. In addition, levels of cAMP and phospho- CREB （pCREB） were increased in the hippocampus of mice deficient in PDE4A or PDE4D, which also produced reversal of Abeta42-induced decreases in pCREB. These datasuggest that PDE4 isoforms have different roles in me-diating alcohol-drinking behavior and memoryin Alzheimer＇ s disease, which are mediated by cAMP/CREB signa- ling. The results indicate PDE4A as a potential new target for alcohol-related dementia, although studies with ani- mal models of alcohol-related dementia are needed to clarify this.
