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首页> 外文期刊>Alcohol >The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety
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The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety

机译：新型，选择性，可穿透脑的神经肽Y Y2受体拮抗剂JNJ-31020028，已在酒精消耗，复发和焦虑的动物模型中进行了测试

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Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorop henyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40. mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0. nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15. mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.
机译：神经肽Y（NPY）信号已被证明可以调节应激反应，并参与酒精摄入和依赖性的调节。本研究探讨了使用新型的血脑屏障渗透剂NPY Y2受体拮抗剂JNJ-31020028（N-（4- {4- [2- [2-（diethylamino）-2-oxo-1 -苯乙基]哌嗪-1-基} -3-氟对苯基）-2-吡啶-3-基苯甲酰胺可能在酒精和焦虑相关的行为模型中实现NPY系统的治疗有用的激活。我们检查了JNJ-31020028在操作性酒精自我管理，压力诱导的寻求酒精恢复以及急性酒精戒断（宿醉）引起的焦虑中的作用。此外，我们在酒精偏爱的遗传动物模型（酒精偏爱（P）大鼠）中测试了其对自愿饮酒的影响。 JNJ-31020028的全身性（0、15、30和40. mg / kg，皮下[sc]）或脑室内（0.0、0.3和1.0。nmol /大鼠）均不影响酒精增强的杠杆压迫或复发。在压力暴露后寻求行为。同样，当测试其对无限制饮酒的大鼠的影响时，对酒精溶液的偏爱被暂时抑制，但不影响自愿饮酒。 JNJ-31020028（15 mg / kg，s.c.）确实抵消了单次推注剂量的酒精对高迷宫产生的焦虑作用，证实了NPY Y2拮抗作用的抗焦虑作用。我们的数据不支持将Y2拮抗作用作为减少饮酒或类似复发的行为的机制，但是观察到的对戒断诱发的焦虑的影响表明，NPY Y2受体拮抗剂可能是戒酒后不良情绪状态的假定治疗方法。

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