Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

在本报告所述期间，对该项目进行了少量的实验室工作。我们与来自纽曼博士的科室和习博士的成瘾生物学部门的PI和实验室人员合作，利用恢复模型探讨了多巴胺D3受体(D3R)拮抗剂VK4-116对羟考酮自我给药和羟考酮引发的寻求羟考酮行为复发的影响。我们还测试了VK4-116对羟考酮抗伤害(即镇痛)作用的影响。羟考酮等处方阿片类药物是临床止痛的高效止痛药，但它们的滥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，开发有效的药物疗法来预防和治疗阿片类药物滥用和成瘾是必不可少的，也是迫切需要的。因此，我们在实验室大鼠中评估了VK4-116的潜在效用，VK4-116是一种新型的高选择性多巴胺D3R拮抗剂，用于预防和治疗处方阿片使用障碍。预先注射VK4-116(5-25 mg/kg，i.p.)剂量依赖性地抑制羟考酮自我给药的获得和维持。VK4-116还降低了羟考酮自身给药的突变点(BP)，使羟考酮剂量-反应曲线下移，抑制了羟考酮消退反应和羟考酮寻找行为的恢复。此外，VK4-116可剂量依赖性地增强羟考酮的抗伤害性作用，减少慢性羟考酮治疗大鼠对纳洛酮的条件性位置厌恶。相比之下，VK4-116对口服蔗糖自给药几乎没有影响。综上所述，这些发现表明D3Rs在阿片奖励中发挥核心作用，并支持VK4-116进一步发展为减轻阿片成瘾发展、降低戒断严重程度和防止复发的有效药物。

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.