Dopamine D_2/3 receptor agonists are less likely to trigger dyskinesias than L-dopa while still offering relief from the motor symptoms of Parkinson's disease (PD). However, these drugs can cause serious impulse control problems and gambling disorders. Adjunctive therapies capable of blocking these side effects without impacting the antiparkinsonian effect would be clinically useful. G-protein-coupled receptor 52 (GPR52) is an orphan Gs-protein-coupled receptor that is coexpressed with striatal D₂ receptors. Activating GPR52 attenuates behaviors associated with increased striatal dopamine release without altering basal function. Iatrogenic gambling disorder may be mediated, at least partly, by striatal dopamine signaling. We therefore investigated whether 2 potent small-molecule GPR52 agonists (BD442618, BD502657) could block the increase in preference for uncertain outcomes caused by acute d-amphetamine and chronic ropinirole, without altering baseline choice patterns. In the rat betting task (rBT), subjects choose between a guaranteed reward (the "wager") versus the 50:50 chance of double the wager or nothing. Although wager size varies across trial blocks, both options are constantly matched for expected value. The effects of BD442618 on the rBT were acutely assessed alone or in combination with d-amphetamine and subsequently in combination with chronic ropinirole. The latter experiment was then repeated with BD502657. BD442618 did not alter baseline decision making but attenuated the increase in preference for uncertainty caused by both acute amphetamine and chronic ropinirole administration. Similarly, BD502657 abrogated chronic ropinirole's effects. These data provide the first evidence that GPR52 agonists may be useful in treating iatrogenic gambling disorder or other conditions hallmarked by hyperdopaminergic states. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

中文翻译：

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GPR52 激动剂减弱了罗匹尼罗诱导的对不确定结果的偏好。

多巴胺 D _2/3受体激动剂比左旋多巴更不可能引发运动障碍，同时仍能缓解帕金森病 (PD) 的运动症状。然而，这些药物会导致严重的冲动控制问题和赌博障碍。能够阻断这些副作用而不影响抗帕金森病作用的辅助疗法在临床上是有用的。G 蛋白偶联受体 52 (GPR52) 是一种孤儿 Gs 蛋白偶联受体，与纹状体 D2 受体共表达。激活 GPR52 会减弱与纹状体多巴胺释放增加相关的行为，而不会改变基础功能。医源性赌博障碍可能至少部分由纹状体多巴胺信号介导。因此，我们研究了 2 种有效的小分子 GPR52 激动剂（BD442618、BD502657) 可以阻止对由急性 d-苯丙胺和慢性罗匹尼罗引起的不确定结果的偏好增加，而不会改变基线选择模式。在老鼠投注任务 (rBT) 中，受试者在保证奖励（“赌注”）与 50:50 的赌注加倍或没有机会之间进行选择。尽管下注大小因试验块而异，但两种选项始终匹配预期价值。BD442618 对 rBT 的影响单独或与 d-苯丙胺组合，随后与慢性罗匹尼罗组合进行了急性评估。然后用BD502657重复后面的实验。BD442618 没有改变基线决策，但减弱了由急性苯丙胺和慢性罗匹尼罗给药引起的不确定性偏好的增加。相似地，BD502657 废除了慢性罗匹尼罗的作用。这些数据提供了第一个证据，证明 GPR52 激动剂可用于治疗医源性赌博障碍或其他以高多巴胺能状态为标志的病症。（PsycInfo 数据库记录 (c) 2020 APA，保留所有权利）。