Zhang Han-Ting, Zhao Yu, Huang Ying, Deng Chengjun, Hopper Allen T, De Vivo Michael, Rose Gregory M, O'Donnell James M
Departments of Behavioral Medicine & Psychiatry and Neurobiology & Anatomy, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA.
Psychopharmacology (Berl). 2006 Jun;186(2):209-17. doi: 10.1007/s00213-006-0369-4. Epub 2006 Apr 4.
Phosphodiesterase-4 (PDE4) has two conformation states based on rolipram binding, the high-affinity rolipram binding state (HARBS) and the low-affinity rolipram binding state (LARBS); their functions remain to be fully explained.
Experiments were carried out to determine the roles of the HARBS and LARBS in the mediation of antidepressant-like effects on behavior.
Two animal models sensitive to antidepressant drugs, the forced-swim test (FST), and the differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, were used to examine the antidepressant-like effects of rolipram, CDP840, and piclamilast, PDE4 inhibitors that interact differentially with the HARBS and LARBS, and MEM1018 and MEM1091, two novel PDE4 inhibitors. Drug discrimination vs rolipram and rolipram competition binding assays also were carried out.
In the FST, rolipram and piclamilast, both at 0.1 mg/kg, produced an antidepressant-like effect, i.e., reduced immobility and increased swimming, whereas, 1 mg/kg of CDP840 or 0.5 mg/kg of MEM1018 or MEM1091 was required to produce a similar effect. Consistent with this, only rolipram and piclamilast produced antidepressant-like effects in rats under the DRL schedule of reinforcement, as evidenced by decreased response rates and increased reinforcement rates. In addition, in rats trained to discriminate rolipram from its vehicle, only rolipram and piclamilast substituted. Finally, [(3)H]rolipram and [(3)H]piclamilast binding analysis revealed that CDP840 and the two novel PDE4 inhibitors MEM1018 and MEM1091 exhibited a lower affinity for the HARBS than did rolipram.
These results suggest that the HARBS of PDE4 is the primary conformation important for antidepressant-like effects on behavior.
磷酸二酯酶-4（PDE4）基于咯利普兰结合存在两种构象状态，即高亲和力咯利普兰结合状态（HARBS）和低亲和力咯利普兰结合状态（LARBS）；它们的功能仍有待充分阐释。
开展实验以确定HARBS和LARBS在介导对行为的抗抑郁样效应中的作用。
使用两种对抗抑郁药物敏感的动物模型，即强迫游泳试验（FST）和低速率差异强化（DRL）72秒操作性程序，来检测咯利普兰、CDP840和吡拉米司特（与HARBS和LARBS有不同相互作用的PDE4抑制剂）以及两种新型PDE4抑制剂MEM1018和MEM1091的抗抑郁样效应。还进行了与咯利普兰的药物辨别以及咯利普兰竞争结合试验。
在FST中，咯利普兰和吡拉米司特均以0.1毫克/千克的剂量产生了抗抑郁样效应，即减少不动时间并增加游泳时间，而CDP840需1毫克/千克或MEM1018或MEM1091需0.5毫克/千克才能产生类似效应。与此一致的是，在DRL强化程序下，只有咯利普兰和吡拉米司特在大鼠中产生了抗抑郁样效应，表现为反应率降低和强化率增加。此外，在经过训练能区分咯利普兰与其溶剂的大鼠中，只有咯利普兰和吡拉米司特能替代。最后，[³H]咯利普兰和[³H]吡拉米司特结合分析表明，CDP840以及两种新型PDE4抑制剂MEM1018和MEM1091对HARBS的亲和力低于咯利普兰。
这些结果表明，PDE4的HARBS是对行为产生抗抑郁样效应的主要重要构象。
