Lai Miaojun, Zhu Huaqiang, Sun Anna, Zhuang Dingding, Fu Dan, Chen Weisheng, Zhang Han-Ting, Zhou Wenhua
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine,Ningbo University,Ningbo 315010,P. R. China.
Departments of Behavioral Medicine & Psychiatry and Physiology & Pharmacology,West Virginia University Health Sciences Center,Morgantown, WV 26506,USA.
Int J Neuropsychopharmacol. 2014 Sep;17(9):1397-407. doi: 10.1017/S1461145714000595. Epub 2014 May 15.
Inhibition of phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes cyclic adenosine monophosphate (cAMP) increases intracellular cAMP/cAMP-response element binding protein (CREB) signaling. Activation of this signaling is considered as an important compensatory response that decreases motivational properties of drugs of abuse. However, it is not known whether PDE4 is involved in heroin seeking. Self-administration of heroin (50 μg/kg/infusion) was performed under the fixed ratio 1 (FR1) schedule for 14 d and then drug seeking was extinguished for 10 d. The progressive ratio schedule was used to evaluate the relative motivational value of heroin reinforcement. After training, the conditioned cue or heroin priming (250 μg/kg) was introduced for the reinstatement of heroin-seeking behavior. Pretreatment (i.p.) with rolipram (0.03-0.3 mg/kg), a prototypical, selective PDE4 inhibitor, failed to inhibit heroin self-administration under the FR1 schedule, but decreased the reward values under the progressive ratio schedule in a dose-dependent manner. In addition, rolipram decreased the reinstatement of heroin seeking induced by cues or heroin priming even at the lowest dose (0.03 mg/kg); in contrast, the highest dose (0.3 mg/kg) of rolipram was required to decrease sucrose reinforcement. Finally, the effects of rolipram on heroin-seeking behavior were correlated with the increases in expression of phosphorylated CREB in the nucleus accumbens. The study demonstrated that rolipram inhibited heroin reward and heroin-seeking behavior. The results suggest that PDE4 plays an essential role in mediating heroin seeking and that PDE4 inhibitors may be used as a potential pharmacotherapeutic approach for heroin addiction.
磷酸二酯酶4（PDE4）是一种特异性水解环磷酸腺苷（cAMP）的酶，抑制该酶可增强细胞内cAMP/环磷酸腺苷反应元件结合蛋白（CREB）信号传导。这种信号传导的激活被认为是一种重要的代偿反应，可降低滥用药物的动机特性。然而，尚不清楚PDE4是否参与海洛因觅求行为。按照固定比率1（FR1）程序进行为期14天的海洛因自我给药（50μg/kg/输注），然后停药10天以消除药物觅求行为。采用累进比率程序评估海洛因强化的相对动机价值。训练后，引入条件性线索或海洛因激发（250μg/kg）以恢复海洛因觅求行为。用咯利普兰（一种典型的选择性PDE4抑制剂，0.03 - 0.3mg/kg，腹腔注射）预处理，未能抑制FR1程序下的海洛因自我给药，但以剂量依赖的方式降低了累进比率程序下的奖赏价值。此外，咯利普兰即使在最低剂量（0.03mg/kg）时也能减少由线索或海洛因激发诱导的海洛因觅求行为的恢复；相比之下，需要咯利普兰的最高剂量（0.3mg/kg）才能降低蔗糖强化。最后，咯利普兰对海洛因觅求行为的影响与伏隔核中磷酸化CREB表达的增加相关。该研究表明咯利普兰抑制海洛因奖赏和海洛因觅求行为。结果表明，PDE4在介导海洛因觅求中起重要作用，PDE4抑制剂可能作为海洛因成瘾的一种潜在药物治疗方法。
