Ethanol discrimination in aged female monkeys

描述（由申请人提供）：乙醇消费的健康后果是所有年龄组的主要问题。随着美国老龄化人口的增加，了解乙醇对老年人的影响尤为重要。老年女性面临着与月经周期停止相关的变化，这可能是乙醇影响变化的唯一原因。研究表明，老年女性特别容易受到乙醇消费的负面健康后果的影响。这项拟议的研究旨在增加我们对乙醇的主观影响的理解，乙醇是乙醇滥用和依赖的重要组成部分。GABA（A）受体对GABA效应的正性调节是乙醇辨别刺激效应的关键组成部分。目前还不清楚这是否在整个生命周期中是恒定的。乙醇的区别性刺激效应可能会随着人们对药物的经验积累而改变，或者因为调节乙醇效应的生理机制随着成熟而改变。我建议使用K.A.博士先前使用的方案，在未接触乙醇的老年食蟹猴中测量乙醇的辨别刺激效应。资助评估年轻成年猴子的乙醇辨别能力及其受体机制。食蟹猴是有用的受试者，因为它们具有类似的月经周期、绝经前后的激素分布，并且与人类类似地代谢乙醇。在药物辨别程序中，训练猴子在给予乙醇后按下一个杠杆，在给予水后按下另一个杠杆;两种物质都通过饲管直接输送到胃中，因此味觉不能指导杠杆按压。只有在按下正确的杠杆后才能输送食物。对猴进行培训，以在乙醇给药后可靠地选择乙醇适当水平，并在水给药后可靠地选择水适当水平。然后，我将评估他们的敏感性的歧视性刺激效应的乙醇和替代三个孕酮衍生物。这些孕酮衍生物由卵巢产生，积极调节GABA（A）受体，三种异构体中的两种在年轻成年雌性猴中替代乙醇。在年轻的成年雌猴月经周期的黄体期，其预后水平和对乙醇的区别性刺激效应的敏感性达到峰值。预后随着年龄和绝经而下降。这些数据将表明，是否有区别的刺激效应的乙醇的受体机制不同的年轻和老年猴子，以及它们是否受到激素耗竭后，cardiacally-induced更年期。

DESCRIPTION (provided by applicant): The health consequences of ethanol consumption are a major concern for all age groups. As the U.S. aging population increases, it is especially important to understand how ethanol affects older people. Aged females face changes associated with the cessation of menstrual cycles that could uniquely contribute to changes in the effects of ethanol. Research shows that aged females are particularly at risk for the negative health consequences of ethanol consumption. The proposed research aims to increase our understanding of the subjective effects of ethanol, an important component of ethanol abuse and dependence. Positive modulation of the effects of GABA at the GABA(A) receptor is a critical component of the discriminative stimulus effects of ethanol. It is unknown whether this is constant across the lifespan. The discriminative stimulus effects of ethanol might change as people accumulate experience with the drug, or because the physiological mechanisms mediating the effects of ethanol change with maturation. I propose to measure the discriminative stimulus effects of ethanol in aged cynomolgus monkeys that are naive to ethanol with protocols previously used by Dr. K.A. Grant to assess ethanol discrimination and its receptor mechanisms in young adult monkeys. Cynomologus monkeys are useful subjects because they have similar menstrual cycles, hormonal profiles pre- and post- menopause, and metabolize ethanol similarly to humans. In the drug discrimination procedure, monkeys are trained to press one lever after administration of ethanol and another after water; both substances are delivered directly into the stomach via feeding tube so that taste cannot direct lever pressing. Food is delivered only after presses to the correct lever. The monkeys will be trained to reliably choose the ethanol-appropriate lever after ethanol administration, and the water-appropriate lever after water administration. Then I will assess their sensitivity to the discriminative stimulus effects of ethanol and the substitution of three progesterone derivatives. These progesterone derivatives are produced by the ovaries, positively modulate GABA(A) receptors, and two of the three isomers substitute for ethanol in young adult female monkeys. Progesterone levels, and sensitivity to the discriminative stimulus effects of ethanol, peak during young adult female monkeys' luteal phase of their menstrual cycle. Progesterone declines with age and menopause. These data will indicate whether the receptor mechanisms for the discriminative stimulus effects of ethanol differ between young and aged monkeys, and whether they are affected by hormonal depletion following surgically-induced menopause.