Ontogenetic changes in ethanol's motivational properties: Involvement of the kapp

描述（由申请人提供）：人类胎儿酒精暴露被认为是青春期和成年期酒精滥用的可能原因。实验室啮齿动物在出生后前两周暴露于乙醇被广泛用作人类胎儿酒精暴露的实验模型，因为其作为人类胎儿发育晚期神经学模型的公认价值。这种早期接触已被证明会显着增加酒精摄入量以后的生活。对早期乙醇暴露敏感的神经机制以及导致报告的乙醇摄入倾向增加的神经机制尚待研究。内源性强啡肽/κ阿片受体系统是极大的兴趣，由于其可能参与减少乙醇的摄入量，通过调节其厌恶的性质。有一些实验证据，尽管仍然有限，强啡肽/κ阿片受体系统的动机特性在个体发育过程中发生变化，新生大鼠和婴儿大鼠发现κ阿片受体的激活具有食欲，成年大鼠表现出厌恶反应。这些研究结果，反过来，建议个体发育差异的κ阿片受体参与乙醇摄入量和强化的基础上，推测，个体发育的变化，动机特性的强啡肽/κ阿片受体系统。目前的建议将测试的假设，kappa阿片系统的动机属性从食欲到厌恶的开关在出生后第2周，与此开关是平行的个体发育增加乙醇的厌恶属性的敏感性。在生命早期暴露于乙醇，特别是在强啡肽/κ阿片受体系统发挥介导食欲强化作用的时期，改变了该系统的厌恶性动机特性，这种改变有助于消耗大量乙醇的倾向，而不会在个体发育后期经历其厌恶性后果。 公共卫生相关性：生命早期暴露于酒精是未来使用和滥用药物的主要因素。kappa/强啡肽阿片系统似乎在调节成年期乙醇的厌恶性方面起着关键作用。这个系统的功能可能会因为早期酒精暴露而改变。拟议的实验将剖析乙醇和kappa/强啡肽系统在生命的前两周内的动机特性的变化。此外，这些研究将探讨早期乙醇暴露对乙醇和κ阿片系统的动机特性的可能影响。

DESCRIPTION (provided by applicant): Fetal alcohol exposure in humans is recognized as a likely contributor to alcohol abuse during adolescence and adulthood. Exposure to ethanol in laboratory rodents during the first two postnatal weeks is widely used as an experimental model of human fetal alcohol exposure, given its accepted value as a neurological model for the third trimester of human fetal development. Such early exposure has been shown to significantly increase ethanol intake later in life. The neural mechanisms susceptible to early ethanol exposure and responsible for the reported increased propensity for ethanol intake are yet to be investigated. The endogenous dynorphin/kappa opioid receptor system is of great interest due to its possible involvement in diminishing ethanol intake through modulation of its aversive properties. There is some experimental evidence, although still limited, that motivational properties of the dynorphin/kappa opioid receptor system change across ontogeny, with newborn and infant rats finding activation of kappa opioid receptors appetitive and adult rats demonstrating aversive responding. These findings, in turn, suggest ontogenetic differences in the kappa opioid receptor involvement in ethanol intake and reinforcement based, presumably, on ontogenetic changes in motivational properties of the dynorphin/ kappa opioid receptor system. The present proposal will test the hypothesis that the motivational properties of the kappa opioid system switch from appetitive to aversive during the 2nd postnatal week, with this switch being parallel to an ontogenetic increase in sensitivity to the aversive properties of ethanol. Exposure to ethanol early in life, especially during the period when the dynorphin/kappa opioid receptor system functions to mediate appetitive reinforcement, alters the aversive motivational properties of this system, with this alteration contributing to the propensity to consume large amounts of ethanol without experiencing its aversive consequences later in ontogeny. PUBLIC HEALTH RELEVANCE: Exposure to alcohol early in life is a major contributing factor to future use and abuse of the drug. The kappa/dynorphin opioid system seems to be critically involved in modulating the aversive properties of ethanol during adulthood. The function of this system may change as a result of early alcohol exposure. The proposed experiments will dissect the changes in the motivational properties of ethanol and the kappa/dynorphin system across the first two weeks of life. Furthermore, these studies will investigate possible effect of early ethanol exposure on the motivational properties of ethanol and kappa opioid system.