Data from: Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats

Chromatin remodelling is integral to the formation of long-term memories. Recent evidence suggests that histone modification may play a role in the persistence of memories associated with drug use. The present series of experiments aimed to examine the effect of histone deacetylase (HDAC) inhibition on the extinction and reinstatement of nicotine self-administration. Rats were trained to intravenously self-administer nicotine for 12 days on a fixed-ratio 1 schedule. In Experiment 1, responding was then extinguished through removal of nicotine and response-contingent cues. After each extinction session, the HDAC inhibitor, sodium butyrate (NaB), was administered immediately, or six hours after each session. In Experiment 2, response-contingent cues remained available across extinction to increase rates of responding during this phase, and NaB was administered immediately after the session. Finally, in Experiment 3, the effect of NaB treatment on extinction of responding for sucrose pellets was assessed. Across all experiments reinstatement to the cue and/or the reward itself was then tested. In the first experiment, treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately, but not six hours after each extinction session. When administered after cue-extinction (Expt. 2), NaB treatment specifically facilitated the rate of extinction across sessions, indicating that HDAC inhibition enhanced consolidation of the extinction memory. In contrast, there was no effect of NaB on the extinction and reinstatement of sucrose-seeking (Expt. 3), indicating that the observed effects are specific to a drug context. These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.

染色质重塑（chromatin remodelling）对于长期记忆的形成至关重要。近期研究证据表明，组蛋白修饰（histone modification）或在药物成瘾相关记忆的维持中发挥作用。本系列实验旨在探究组蛋白去乙酰化酶（histone deacetylase, HDAC）抑制对尼古丁自身给药行为消退与复吸的影响。实验大鼠先接受为期12天的固定比率1（fixed-ratio 1, FR1）程序训练，完成对应操作即可获得静脉注射尼古丁的奖赏。在实验1中，通过撤除尼古丁及操作相关条件性线索，使大鼠的尼古丁寻求行为逐步消退。每次消退训练结束后，分别即刻或6小时后给予组蛋白去乙酰化酶抑制剂丁酸钠（sodium butyrate, NaB）。实验2中，在消退阶段保留操作相关条件性线索以提升该阶段的操作反应率，并在每次消退训练结束后即刻给予丁酸钠。最后，实验3旨在评估丁酸钠给药对蔗糖颗粒寻求行为消退的影响。所有实验均后续测试了条件性线索及/或奖赏本身诱发的复吸行为。实验1结果显示，即刻给药组的丁酸钠处理可显著减弱尼古丁单独及尼古丁+条件性线索诱发的复吸行为，而6小时给药组无此效应。在经过条件性线索消退训练后给药（实验2），丁酸钠处理可特异性提升各次消退训练中的反应消退速率，表明组蛋白去乙酰化酶抑制可增强消退记忆的巩固过程。与之相反，丁酸钠对蔗糖寻求行为的消退与复吸均无显著影响（实验3），表明本研究观察到的效应仅特异性存在于药物成瘾相关情境中。本研究结果首次证实，组蛋白去乙酰化酶抑制可促进静脉自身给药成瘾药物的寻求行为消退，并进一步凸显了组蛋白去乙酰化酶抑制剂在药物成瘾治疗中的应用潜力。