Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
Psychopharmacology (Berl). 2019 Jan;236(1):517-529. doi: 10.1007/s00213-018-5122-2. Epub 2018 Nov 28.
A challenge in treating substance use disorder is that successful treatment often does not persist, resulting in relapse and continued drug seeking. One approach to persistently weaken drug-seeking behaviors is to pair exposure to drug-associated cues or behaviors with delivery of a compound that may strengthen the inhibition of the association between drug cues and behavior.
We evaluated whether a selective histone deacetylase 3 (HDAC3) inhibitor could promote extinction and weaken contextual control of operant drug seeking after intravenous cocaine self-administration.
Male Long-Evans rats received a systemic injection of the HDAC3 inhibitor RGFP966 either before or immediately after the first extinction session. Persistence of extinction was tested over subsequent extinction sessions, as well as tests of reinstatement that included cue-induced reinstatement, contextual renewal, and cocaine-primed reinstatement. Additional extinction sessions occurred between each reinstatement test. We also evaluated effects of RGFP966 on performance and motivation during stable fixed ratio operant responding for cocaine and during a progressive ratio of reinforcement.
RGFP966 administered before the first extinction session led to significantly less responding during subsequent extinction and reinstatement tests compared to vehicle-injected rats. Follow-up studies found that these effects were not likely due to a performance deficit or a change in motivation to self-administer cocaine, as injections of RGFP966 had no effect on stable responding during a fixed or progressive ratio schedule. In addition, RGFP966 administered just after the first extinction session had no effect during early extinction and reinstatement tests, but weakened long-term responding during later extinction sessions.
These results suggest that a systemic injection of a selective HDAC3 inhibitor can enhance extinction and suppress reinstatement after cocaine self-administration. The finding that behavioral and pharmacological manipulations can be combined to decrease drug seeking provides further potential for treatment by epigenetic modulation.
治疗物质使用障碍的一个挑战是，成功的治疗往往不能持续，导致复发和持续的药物寻求。一种持续削弱药物寻求行为的方法是将暴露于药物相关线索或行为与递送至可能增强药物线索与行为之间关联的抑制的化合物配对。
我们评估了一种选择性组蛋白去乙酰化酶 3 (HDAC3) 抑制剂是否可以促进可卡因自我给药后的消退并削弱操作性药物寻求的情境控制。
雄性长耳大仓鼠在第一次消退训练前或结束后立即接受 HDAC3 抑制剂 RGFP966 的全身注射。在随后的消退训练中测试消退的持久性，以及包括线索诱导复燃、情境更新和可卡因引发复燃的复燃测试。在每次复燃测试之间进行额外的消退训练。我们还评估了 RGFP966 对稳定固定比率可卡因操作反应和递增强化比率期间的表现和动机的影响。
与接受载体注射的大鼠相比，在第一次消退训练前给予 RGFP966 会导致随后的消退和复燃测试中的反应明显减少。后续研究发现，这些效应不太可能是由于表现缺陷或自我给药动机的改变，因为 RGFP966 注射对固定或递增比率方案期间的稳定反应没有影响。此外，在第一次消退训练后立即给予 RGFP966 在早期消退和复燃测试中没有效果，但在后期消退训练中减弱了长期反应。
这些结果表明，系统注射选择性 HDAC3 抑制剂可以增强可卡因自我给药后的消退并抑制复燃。行为和药理学操作的结合可以减少药物寻求的发现为通过表观遗传调节提供了进一步的治疗潜力。
