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. ? ? ?
