Escalated oxycodone self-administration is associated with activation of specific gene networks in the rat dorsal striatum

The number of individuals diagnosed with opioid use disorder (OUD) has risen steeply because of the increased prescribing of opioid drugs like oxycodone for chronic pain relief. OUD is characterized by loss of control of drug taking, continued drug use in the presence of adverse consequences, and repeated relapses to drug taking. Repeated exposure to oxycodone self-administration can lead to addiction in certain rats while others remain unaffected. Understanding the molecular mechanisms between these two groups holds promise for developing strategies to combat addiction. To identify signaling pathways associated with oxycodone addition, this study used male Sprague-Dawley rats to self-administer oxycodone for 20 days according to short-(ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized after 2 hours of self-administration cessation and their dorsal striata were used for RNA sequencing analysis. LgA rats escalated their oxycodone intake and developed into 2 phenotypes, named long-access high (LgA-H, addicted) and long-access lower (LgA-L, non-addicted) rats, based on the level of escalation and drug taken during the self-administration experiment. RNA sequencing revealed many differentially expressed genes in the oxycodone-addicted rats in comparison to other groups. DAVID analysis indicated that some of these genes were involved in potassium transport, ATP binding, and regulation of synaptic processes. Ingenuity pathway analysis (IPA) revealed previous involvement of some genes in OUD and cognitive processes. RNA sequencing and RT-PCR analysis of dorsal striatum samples unveiled a significant upregulation of potassium channel genes Kcnma1, Kcnk9, Kcnq1, Kcnd3, and Kcng3 in LgA-H rats, which was corelated with oxycodone intake. We also identified increased expression for Cldn3, Serping1, and Serpinh1 in ShA rats. Taken together, these observations identified potassium channels as potential targets for the treatment of oxycodone use disorder.因羟考酮等阿片类药物用于慢性疼痛缓解的处方量持续攀升，被诊断为阿片类药物使用障碍（Opioid Use Disorder, OUD）的人数大幅上升。该障碍的核心特征为药物使用失控、即便伴随不良后果仍持续用药，且反复出现复吸行为。对大鼠反复施行羟考酮自身给药操作，可使部分个体产生成瘾行为，其余大鼠则不受影响。解析这两组大鼠的分子差异机制，有望为开发对抗成瘾的干预策略提供新方向。为鉴定与羟考酮成瘾相关的信号通路，本研究选用雄性斯普拉格-道利（Sprague-Dawley, SD）大鼠，按照短时程给药（ShA，3小时）与长时程给药（LgA，9小时）范式，让大鼠自行施用羟考酮，持续20天。在自身给药停止2小时后，对大鼠实施安乐死，取其背侧纹状体组织进行RNA测序分析。长时程给药组大鼠的羟考酮摄入量随实验推进逐渐递增，并根据自身给药实验中的摄入量递增程度与用药总量，分化为两种表型：长时程高摄入组（LgA-H，成瘾组）与长时程低摄入组（LgA-L，非成瘾组）。RNA测序结果显示，相较于其余组别，羟考酮成瘾大鼠体内存在大量差异表达基因。DAVID分析表明，部分差异表达基因参与钾离子转运、ATP结合以及突触过程调控。经典通路分析（Ingenuity Pathway Analysis, IPA）显示，部分基因此前已被证实与阿片类药物使用障碍及认知过程相关。对背侧纹状体组织的RNA测序与实时荧光定量PCR（RT-PCR）分析显示，长时程高摄入组大鼠体内的钾离子通道基因Kcnma1、Kcnk9、Kcnq1、Kcnd3及Kcng3均出现显著上调，且该上调水平与羟考酮摄入量呈显著相关。本研究同时发现，短时程给药组大鼠体内的Cldn3、Serping1及Serpinh1基因表达水平升高。综上，本研究结果证实钾离子通道可作为治疗羟考酮使用障碍的潜在靶点。