Makhay M M, Houslay M D, O'Donnell J M
Acadia Pharmaceuticals, 3911 Sorrento Valley Boulevard, San Diego, CA 92121-1402, USA.
Psychopharmacology (Berl). 2001 Nov;158(3):297-304. doi: 10.1007/s002130100878.
Rolipram, an inhibitor of cyclic AMP phosphodiesterase (PDE4) produces discriminative stimulus effects in rats. These effects may be related to a wide range of central nervous system effects described previously.
The purposes of the present study were to: (i) assess the specificity of the discriminative stimulus effects of rolipram; (ii) examine the role of beta adrenergic receptors; (iii) assess the effects of imipramine and nisoxetine; and (iv) determine whether SKF 38393, a compound which also increases cAMP levels, substitutes for rolipram.
Rats were trained to discriminate 0.1 mg/kg rolipram from its vehicle in a two-lever task. Following discrimination training, substitution and antagonism tests were carried out.
In generalization tests, the PDE4 inhibitors ICI 63,197 and Ro 20-1724 substituted for rolipram in a dose-dependent manner (substitution at 0.3 mg/kg and 3 mg/kg, respectively). The selective inhibitors of PDE1, PDE2, and PDE5/6 did not substitute for rolipram; however, a dose of 10 mg/kg of the PDE3 inhibitor milrinone did substitute. The beta adrenergic agonists clenbuterol and dobutamine at least partially substituted for rolipram (0.1 mg/kg and 18 mg/kg, respectively). By contrast, the D1 dopaminergic agonist SKF 38393 and the monoamine uptake inhibitors imipramine and nisoxetine were ineffective (at doses up to 3, 10, and 10 mg/kg, respectively).
The present results indicate that the discriminative stimulus effects of rolipram are related to the inhibition of the hydrolytic activity of PDE4. Generalized increases in cyclic nucleotides do not appear to be sufficient for producing rolipram-like effects. It appears that a mechanism involving beta adrenergic receptors may contribute to the effects of rolipram, consistent with previous neuropharmacological data. Finally, the discriminative stimulus effects of rolipram appear to be unrelated to its antidepressant-like effect, but may provide a surrogate marker for central nervous system-related side effects of PDE4 inhibitors.
咯利普兰，一种环磷酸腺苷磷酸二酯酶（PDE4）抑制剂，在大鼠中产生辨别性刺激效应。这些效应可能与先前描述的广泛的中枢神经系统效应有关。
本研究的目的是：（i）评估咯利普兰辨别性刺激效应的特异性；（ii）研究β肾上腺素能受体的作用；（iii）评估丙咪嗪和尼索西汀的效应；（iv）确定同样能提高环磷酸腺苷水平的化合物SKF 38393是否能替代咯利普兰。
在双杠杆任务中训练大鼠区分0.1mg/kg咯利普兰与其溶媒。辨别训练后，进行替代和拮抗试验。
在泛化试验中，PDE4抑制剂ICI 63,197和Ro 20 - 1724以剂量依赖方式替代咯利普兰（分别在0.3mg/kg和3mg/kg时替代）。PDE1、PDE2和PDE5/6的选择性抑制剂不能替代咯利普兰；然而，10mg/kg剂量的PDE3抑制剂米力农可以替代。β肾上腺素能激动剂克仑特罗和多巴酚丁胺至少部分替代咯利普兰（分别为0.1mg/kg和18mg/kg）。相比之下，D1多巴胺能激动剂SKF 38393以及单胺摄取抑制剂丙咪嗪和尼索西汀无效（分别在高达3、10和10mg/kg的剂量下）。
目前的结果表明，咯利普兰的辨别性刺激效应与PDE4水解活性的抑制有关。环核苷酸的普遍增加似乎不足以产生类似咯利普兰的效应。看来涉及β肾上腺素能受体的机制可能促成咯利普兰的效应，这与先前的神经药理学数据一致。最后，咯利普兰的辨别性刺激效应似乎与其抗抑郁样效应无关，但可能为PDE4抑制剂的中枢神经系统相关副作用提供一个替代标志物。
