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首页> 外文期刊>The international journal of neuropsychopharmacology >The phosphodiesterase-4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or heroin priming in rats
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The phosphodiesterase-4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or heroin priming in rats

机译：磷酸二酯酶4抑制剂rolipram减弱了线索或海洛因引发引发的海洛因寻求行为

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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.
机译：磷酸二酯酶4（PDE4）的抑制，这是一种特异性水解环状单磷酸腺苷（cAMP）的酶，可增加细胞内cAMP / cAMP反应元件结合蛋白（CREB）的信号传导。该信号的激活被认为是重要的补偿性反应，其降低了滥用药物的动机特性。但是，尚不清楚PDE4是否参与海洛因搜寻。按照固定比例1（FR1）时间表进行海洛因（50μg/ kg /输注）的自我给药14 d，然后消灭药物10 d。进步比率表被用来评估海洛因强化的相对动机价值。训练后，引入条件提示或海洛因引发（250μg/ kg）来恢复海洛因寻找行为。用典型的选择性PDE4抑制剂咯利普兰（0.03-0.3 mg / kg）进行的预处理（ip）在FR1方案下未能抑制海洛因自我给药，但在渐进比例方案下以剂量依赖的方式降低了奖励值。此外，即使在最低剂量（0.03 mg / kg）下，咯利普兰也降低了线索或海洛因引发引发的海洛因恢复。相反，需要最大剂量的罗利普兰（0.3 mg / kg）来减少蔗糖的强化作用。最后，咯利普兰对海洛因寻求行为的影响与伏伏核中磷酸化CREB表达的增加有关。研究表明，咯利普兰抑制海洛因奖赏和海洛因寻找行为。结果表明，PDE4在介导海洛因寻找中起着至关重要的作用，PDE4抑制剂可作为海洛因成瘾的潜在药物治疗方法。

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