Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

在本报告所述期间，对这个项目进行了少量的实验室工作。我们与Newman博士的部门和Xi博士的成瘾生物学部门的pi和实验室人员合作，利用恢复模型探索了多巴胺D3受体（D3R）拮抗剂VK4-116对羟考酮自我给药和羟考酮引发的羟考酮寻求行为复发的影响。我们还测试了VK4-116对羟考酮抗痛感（即镇痛）作用的影响。处方阿片类药物如羟考酮是临床疼痛管理的高效镇痛药，但它们的误用和滥用导致了目前阿片类药物在美国的流行。为了改善这一公共卫生危机，开发预防和治疗阿片类药物滥用和成瘾的有效药物疗法是必不可少的，也是迫切需要的。因此，我们在实验室大鼠中评估了VK4-116（一种新型的高选择性多巴胺D3R拮抗剂）在预防和治疗处方阿片类药物使用障碍方面的潜在效用。VK4-116预处理（5-25 mg/kg, i.p）呈剂量依赖性地抑制羟考酮自我给药的获得和维持。VK4-116还降低了渐进式比例强化方案下羟考酮自我给药的断点（BP），使羟考酮剂量-反应曲线向下移动，抑制羟考酮消退反应和羟考酮寻求行为的恢复。此外，VK4-116预处理剂量依赖性地增强了羟考酮的抗伤害感受作用，并减少了长期服用羟考酮的大鼠纳洛酮沉淀的条件性地方厌恶。相比之下，VK4-116对口服蔗糖自我给药的影响很小。综上所述，这些发现表明D3Rs在阿片类药物奖励中发挥着核心作用，并支持VK4-116作为缓解阿片类药物成瘾发展、降低戒断严重程度和预防复发的有效药物的进一步发展。

During the present reporting period, modest laboratory work was conducted on this project. Working in collaboration with PIs and lab personnel from Dr. Newman's section and Dr. Xi's Addiction Biology Unit, we explored the effect of the dopamine D3 receptor (D3R) antagonist VK4-116 on oxycodone self-administration and oxycodone-triggered relapse to oxycodone-seeking behavior using the reinstatement model. We also tested the effects of VK4-116 on oxycodone's antinociceptive (i.e., analgesic) effects. Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. We therefore evaluated - in laboratory rats - the potential utility of VK4-116, a novel and highly selective dopamine D3R antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.