Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.
Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Br J Pharmacol. 2020 Oct;177(20):4796-4807. doi: 10.1111/bph.15244. Epub 2020 Sep 17.
Despite widespread abuse of cocaine, there are no approved treatments for cocaine use disorder. Chronic cocaine use is associated with up-regulated dopamine D receptor expression in the brain. Therefore, most D -based medication development has focused on D antagonists. However, D antagonists do not attenuate cocaine intake under "easy" self-administration conditions, when response requirements are low. We evaluated a novel, highly selective and metabolically stable D partial agonist, (±)VK4-40, for its efficacy in reducing cocaine intake and relapse to drug seeking.
The impact of (±)VK4-40 on cocaine intake and relapse was evaluated using intravenous self-administration procedures under a fixed-ratio 2 reinforcement schedule and cocaine-primed reinstatement conditions in rats. Optogenetic brain-stimulation reward procedures were used to evaluate the interaction of (±)VK4-40 and cocaine in the mesolimbic dopamine system in mice. Sucrose self-administration in rats and a conditioned place preference paradigm in mice were used to evaluate the abuse potential of (±)VK4-40 alone and other unwanted effects.
(±)VK4-40 dose-dependently reduced cocaine self-administration and cocaine-primed reinstatement of drug-seeking behaviour. (±)VK4-40 also inhibited cocaine-enhanced brain-stimulation reward caused by optogenetic stimulation of dopamine neurons in the ventral tegmental area. (±)VK4-40 alone decreased brain-stimulation reward but produced neither conditioned place preference nor place aversion. This new D partial agonist also failed to alter oral sucrose self-administration.
The novel D partial agonist, (±)VK4-40 attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D partial agonists as putative treatments for cocaine use disorder.
尽管可卡因被广泛滥用，但目前尚无可卡因使用障碍的获批治疗方法。慢性可卡因使用会导致大脑中多巴胺 D 受体表达上调。因此，大多数基于 D 的药物开发都集中在 D 拮抗剂上。然而，在反应要求较低的“简单”自我给药条件下，D 拮抗剂并不能减弱可卡因的摄入。我们评估了一种新型、高选择性和代谢稳定的 D 部分激动剂（±）VK4-40，以评估其在减少可卡因摄入和药物寻求复吸方面的疗效。
采用静脉自我给药程序，在固定比率 2 强化方案和可卡因激发复吸条件下，评估（±）VK4-40 对可卡因摄入和复吸的影响。利用光遗传学脑刺激奖励程序，评估（±）VK4-40 在小鼠中与可卡因在中脑边缘多巴胺系统中的相互作用。在大鼠中进行蔗糖自我给药和条件性位置偏爱范式，以评估（±）VK4-40 单独使用的滥用潜力和其他不良反应。
（±）VK4-40 剂量依赖性地减少可卡因的自我给药和可卡因激发的觅药行为的复吸。（±）VK4-40 还抑制了光遗传学刺激腹侧被盖区多巴胺神经元引起的可卡因增强的脑刺激奖励。（±）VK4-40 单独使用会降低脑刺激奖励，但既不会产生条件性位置偏好，也不会产生位置厌恶。这种新型 D 部分激动剂也不会改变口服蔗糖的自我给药。
新型 D 部分激动剂（±）VK4-40 可减弱啮齿动物对可卡因的奖赏和复吸，且无明显不良反应。这些发现支持进一步研究 D 部分激动剂作为可卡因使用障碍的潜在治疗方法。
