BACKGROUND Excessive alcohol intake is a serious but preventable public health problem in the United States and worldwide. Alcohol and other substance use disorders occur co-morbid with more generalized reward deficiency disorders, characterized by a reduction in dopamine (DA) signaling within the reward pathway, and classically associated with increased impulsivity, risk taking and subsequent drug seeking behavior. It is postulated that increasing dopamine availability and thus restoring DA homeostasis in the mesocorticolimbic system could reduce the motivation to seek and consume ethanol. Here, we treated animals with a neuro-nutrient, KB220Z also known as Synaptamine, designed to augment DA signaling. METHOD KB220Z was administered to genetically alcohol-preferring (P) adult male and female rats by oral gavage (PO), intraperioneally (IP), or subcutaneously (SQ) for 4 consecutive days at a 3.4 mL/Kg rat equivalent dose and compared to saline (SQ, IP) or water (PO) controls. Subsequent to treatment, lever pressing and consumption of 10 % ethanol or control 3% sucrose during operant responding was assessed using a drinking in the dark multiple scheduled access (DIDMSA) binge drinking protocol. Locomotor and elevated zero maze activity, and DRD2 mRNA expression via in situ hybridization (ISH) were assessed independently following 4 days of a SQ regimen of KB220Z. RESULTS KB220Z administered via IP and SQ markedly and immediately reduced binge drinking of 10 % ethanol in both male and female rats whereas PO administration took at least 3 days to decrease lever pressing for ethanol in both male and female rats. There was no effect of SQ KB220Z on 3% sucrose drinking. Elevated activity in the open field was significantly decreased, and time spent in the open arm of the EZM was moderately reduced. The regimen of SQ KB220Z did not impact the number of DRD2 punctae in neurons of the NAc, but the NAc shell expressed more DRD2 mRNA/cell than NAc core independent of KB220Z. CONCLUSION KB220Z attenuates ethanol drinking and other RDS behaviors in P rats possibly by acting on the dopaminergic system, but not by effecting an increase in NAc DRD2 mRNA expression.

中文翻译：

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推定的前多巴胺调节剂（一种神经营养素）的给药可减轻偏爱酒精的大鼠的酒精摄入。

背景技术在美国和全世界，过量饮酒是严重但可预防的公共健康问题。酒精和其他物质使用障碍与更普遍的奖励缺乏障碍并存，其特点是奖励途径内的多巴胺（DA）信号减少，并且通常与冲动性增加，冒险和随后的寻药行为有关。据推测，增加多巴胺的利用率，从而恢复中皮质糖皮质系统中的DA稳态可能会减少寻找和消耗乙醇的动力。在这里，我们用神经营养素KB220Z（也称为Synaptamine）治疗动物，该营养素旨在增强DA信号传导。方法：KB220Z通过口服管饲法（PO），腹膜内（IP）给予成年酒精偏爱（P）成年雄性和雌性大鼠，或连续连续4天以3.4 mL / Kg大鼠当量剂量皮下注射（SQ），并与生理盐水（SQ，IP）或水（PO）对照进行比较。在治疗之后，使用暗处多次排便（DIDMSA）暴饮酒方案评估手术反应期间的杠杆按压和消耗10％乙醇或对照3％蔗糖的消耗。在KB220Z的SQ方案治疗4天后，通过原位杂交（ISH）独立评估了运动能力和升高的零迷宫活性，以及​​DRD2 mRNA的表达。结果通过IP和SQ施用KB220Z可以显着降低雄性和雌性大鼠中10％乙醇的暴饮暴食，而PO施用至少需要3天才能降低雄性和雌性大鼠对乙醇的杠杆压力。SQ KB220Z对3％的蔗糖饮用量没有影响。在旷野的活动增加明显减少，在EZM开放臂上花费的时间被适度减少。SQ KB220Z的方案不影响NAc神经元中DRD2点的数目，但NAc外壳表达的DRD2 mRNA /细胞比独立于KB220Z的NAc核心更多。结论KB220Z可能通过作用于多巴胺能系统来减轻P大鼠的饮酒和其他RDS行为，但不影响NAc DRD2 mRNA表达的增加。