Perrine Shane A, Alsharif Walid F, Harutyunyan Arman, Kamal Swatabdi, Viola Nerissa T, Gelovani Juri G
Psychiatry and Behavioral Neurosciences, Wayne State University, 6135 Woodward Avenue, Suite 3119, Detroit, MI, USA.
Research Services, John D. Dingell VAMC, Detroit, MI, USA.
Addict Neurosci. 2022 Dec;4. doi: 10.1016/j.addicn.2022.100046. Epub 2022 Nov 8.
Repeated cocaine alters neuronal function in the nucleus accumbens (NAc), a brain region involved in cocaine taking, and in hippocampus (HC), known for contextual and associative learning. [F]TFAHA is a histone deacetylase (HDAC) class IIa-specific radiotracer for positron emission tomography (PET)-imaging developed by our group to study epigenetic mechanisms. Here, [F]TFAHA was used to conduct PET-imaging coupled with computed tomography (CT) of rat brains at baseline and after repeated cocaine intravenous self-administration (cocaine-IVSA) in low-intake versus high-intake cocaine groups. A 3 h-access FR1-schedule of cocaine-IVSA (0.5 mg/kg/infusion) for 12 continuous days was used with male Sprague Dawley rats following jugular vein catheterization. PET/CT neuroimaging with [F]TFAHA was acquired in a dynamic mode over 40 min post-radiotracer administration at baseline and on day 12 of cocaine-IVSA using a longitudinal, repeated design. This study shows that high-cocaine intake significantly decreases class IIa HDAC expression-activity in NAc, while low-cocaine intake significantly decreases expression-activity in HC in male rats. These findings suggest the individual rats with low-cocaine intake had epigenetic changes in HC, where drug-associative changes occur. Alternatively, individuals with high-cocaine intake had robust epigenetic changes in NAc, where rewared-related behaviors originate. These findings are the first longitudinal data obtained to implicate class IIa HDACs in the persistent behavioral effects of cocaine. Furthermore, our results are consistent with published research implicating class IIa HDACs in cocaine-induced brain changes and studies suggesting a relationship between an individual's drug-taking behavior and regional pattern of epigenetic changes in the brain.
反复使用可卡因会改变伏隔核（NAc）中的神经元功能，伏隔核是一个与可卡因摄取有关的脑区，同时也会改变海马体（HC）中的神经元功能，海马体以情境学习和联想学习而闻名。[F]TFAHA是我们团队开发的一种用于正电子发射断层扫描（PET）成像的IIa类组蛋白去乙酰化酶（HDAC）特异性放射性示踪剂，用于研究表观遗传机制。在这里，[F]TFAHA被用于在低剂量与高剂量可卡因组中，对大鼠大脑进行基线时以及反复静脉注射可卡因自我给药（可卡因-IVSA）后，结合计算机断层扫描（CT）的PET成像。对雄性Sprague Dawley大鼠进行颈静脉插管后，采用连续12天、每天3小时的可卡因-IVSA（0.5毫克/千克/输注）、固定比率为1的给药方案。在基线时以及可卡因-IVSA第12天，在注射放射性示踪剂后40分钟内，以动态模式使用纵向重复设计获取[F]TFAHA的PET/CT神经成像。这项研究表明，高剂量可卡因摄入会显著降低雄性大鼠伏隔核中IIa类HDAC的表达活性，而低剂量可卡因摄入会显著降低海马体中的表达活性。这些发现表明，低剂量可卡因摄入的个体在海马体中发生了表观遗传变化，而药物联想变化就发生在海马体中。或者说，高剂量可卡因摄入的个体在伏隔核中发生了强烈的表观遗传变化，而奖赏相关行为就起源于伏隔核。这些发现是首次获得的纵向数据，表明IIa类HDAC与可卡因的持续行为效应有关。此外，我们的结果与已发表的研究一致，这些研究表明IIa类HDAC与可卡因引起的大脑变化有关，并且有研究表明个体的药物摄取行为与大脑表观遗传变化的区域模式之间存在关联。
