Monsey Melissa S, Ruiz Sonia G, Taylor Jane R
Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States.
Department of Psychology, Yale University, New Haven, CT, United States.
Front Behav Neurosci. 2020 Jan 8;13:281. doi: 10.3389/fnbeh.2019.00281. eCollection 2019.
Exposure to drug-related cues often disrupts abstinence from cocaine use by triggering memories of drug effects, leading to craving and possible relapse. One prospective method of treatment is weakening cocaine-associated memories impairment of memory reconsolidation. Previous experiments have shown that systemic injection of the amnestic agent garcinol impairs the reconsolidation of cocaine-cue memories in a temporally constrained, cue-specific, and persistent manner. Here, we investigated garcinol's effect on cocaine-cue memory reconsolidation when administered to the lateral nucleus of the amygdala (LA), as well as its epigenetic activity following systemic garcinol administration and also when given in conjunction with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor. Rats received 12 days of cocaine self-administration training during which time an active lever press resulted in an i.v. cocaine infusion that was concurrently paired with the presentation of a light/tone cue. After 8 days of lever extinction, rats received a memory reactivation session followed by a cue-induced reinstatement test. Intra-LA garcinol following memory reactivation significantly impaired reconsolidation only if the memory was reactivated. Additional studies revealed a significant reduction in histone H3 K27 acetylation and reduced expression of the immediate-early genes Arc and Egr-1 in the LA. When administered alone, TSA enhanced the reinstatement of a cocaine-cue memory, an effect that was prevented when garcinol was concurrently administered. These data indicate the LA is a key structure responsive to garcinol, suggest that one of garcinol's mechanisms of action is through the reduction of memory-related gene expression in the LA, implicate changes in histone acetylation in memory reconsolidation, and support garcinol as a potential therapeutic tool for sustaining abstinence.
接触与药物相关的线索通常会通过触发对药物效果的记忆来破坏可卡因使用的戒断状态，导致渴望并可能复发。一种前瞻性的治疗方法是削弱与可卡因相关的记忆——记忆再巩固的损害。先前的实验表明，全身注射遗忘剂藤黄酚会以时间受限、线索特异性和持久的方式损害可卡因线索记忆的再巩固。在这里，我们研究了将藤黄酚注射到杏仁核外侧核（LA）时对可卡因线索记忆再巩固的影响，以及全身注射藤黄酚后以及与组蛋白脱乙酰酶（HDAC）抑制剂曲古抑菌素A（TSA）联合使用时其表观遗传活性。大鼠接受了12天的可卡因自我给药训练，在此期间，主动按压杠杆会导致静脉注射可卡因，并同时伴有光/音线索的呈现。在杠杆消退8天后，大鼠接受记忆重新激活训练，随后进行线索诱导的复吸测试。只有在记忆被重新激活的情况下，记忆重新激活后注射到LA内的藤黄酚才会显著损害再巩固。进一步的研究表明，LA中组蛋白H3 K27乙酰化显著降低，即刻早期基因Arc和Egr-1的表达也降低。单独使用时，TSA会增强可卡因线索记忆的复吸，而当同时使用藤黄酚时，这种效果会被阻止。这些数据表明LA是对藤黄酚有反应的关键结构，表明藤黄酚的作用机制之一是通过降低LA中与记忆相关的基因表达，暗示组蛋白乙酰化变化与记忆再巩固有关，并支持藤黄酚作为维持戒断的潜在治疗工具。
