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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZAA1-HH (11))
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Grakalic, Ivana
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Oregon Health and Science University
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Helms, Christa M; McCracken, Aubrey D; Heichman, Sharon L et al. (2013) Ovarian hormones and the heterogeneous receptor mechanisms mediating the discriminative stimulus effects of ethanol in female rats. Behav Pharmacol 24:95-104
Helms, Christa M; Messaoudi, Ilhem; Jeng, Sophia et al. (2012) A longitudinal analysis of circulating stress-related proteins and chronic ethanol self-administration in cynomolgus macaques. Alcohol Clin Exp Res 36:995-1003
Helms, Christa M; Grant, Kathleen A (2011) The effect of age on the discriminative stimulus effects of ethanol and its GABA(A) receptor mediation in cynomolgus monkeys. Psychopharmacology (Berl) 216:333-43
Cuzon Carlson, Verginia C; Seabold, Gail K; Helms, Christa M et al. (2011) Synaptic and morphological neuroadaptations in the putamen associated with long-term, relapsing alcohol drinking in primates. Neuropsychopharmacology 36:2513-28
Helms, Christa M; Rogers, Laura S M; Grant, Kathleen A (2009) Antagonism of the ethanol-like discriminative stimulus effects of ethanol, pentobarbital, and midazolam in cynomolgus monkeys reveals involvement of specific GABA(A) receptor subtypes. J Pharmacol Exp Ther 331:142-52