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关注的主要问题。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，老年女性尤其容易受到酒精消费对健康造成的负面影响。提出的研究旨在增加我们对乙醇的主观影响的理解，这是乙醇滥用和依赖的一个重要组成部分。GABA对GABA(A)受体的正向调节作用是乙醇鉴别刺激作用的关键组成部分。目前尚不清楚这在整个生命周期中是否不变。乙醇的鉴别刺激作用可能随着人们对药物的积累而改变，或者因为调节乙醇作用的生理机制随着成熟而改变。我建议使用K.A. Grant博士先前在年轻成年猴子中评估乙醇辨别及其受体机制时使用的方案来测量乙醇对未接触乙醇的老年食蟹猴的辨别刺激效应。食蟹猴是有用的研究对象，因为它们有类似的月经周期，绝经前后的激素特征，以及与人类相似的乙醇代谢。在药物识别过程中，猴子被训练在给药后按一个杠杆，在给药后按另一个杠杆；这两种物质都是通过喂食管直接进入胃中，所以味觉不能直接按压杠杆。只有按到正确的杠杆，食物才会送到。将训练猴子在给乙醇后可靠地选择乙醇适宜的杠杆，在给水后可靠地选择水适宜的杠杆。然后，我将评估它们对乙醇和三种黄体酮衍生物替代的鉴别刺激效应的敏感性。这些黄体酮衍生物由卵巢产生，正向调节GABA(A)受体，三种异构体中的两种在年轻成年雌性猴子中替代乙醇。孕酮水平和对乙醇辨别刺激效应的敏感性在年轻成年雌猴月经周期的黄体期达到峰值。黄体酮随着年龄和更年期而下降。这些数据将表明乙醇的鉴别刺激作用的受体机制在年轻猴子和老年猴子之间是否不同，以及它们是否受到手术诱导绝经后激素消耗的影响。

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.