Family History and Spinophilin Genotype Influence NMDA Receptor Function and Ethanol Response
This Project builds from our original CTNA Project to explore the hypothesis that individuals with a family history positive for alcohol dependence (FHP), experience an alteration in the reward valence of ethanol (more positive effects and reduced negative effects) compared to family history negative (FHN) age-matched subjects. This project builds on basic science evidence that the discriminative stimulus effects of ethanol reflect a composite of its pharmacologic effects in the brain. Therefore variation in genes that code for key ethanol targets in the brain or downstream signal transduction mechanisms may increase or decrease the risk for alcoholism by altering a component of the discriminative stimulus effects of ethanol. In this case, we are studying the NMDA receptor, an important ethanol target in the brain. This study will test the hypothesis that both ketamine and alcohol response (using the alcohol clamp procedure to minimize pharmacokinetic issues) will be similarly influenced by family history of alcoholism and by the spinophilin SNP, strengthening the hypothesis that the NMDA receptor antagonist component of ethanol action contributes to the abuse liability of ethanol.
Methods
This study is a two phased study: Phase I: a double-blind, placebo controlled evaluation of the perceptual, neurophysiologic and cognitive effects of an intravenous (IV) ethanol clamp infusion; and Phase II; a double-blind, placebo controlled evaluation of the perceptual, cognitive, and neurophysiologic effects of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, in healthy individuals at increased familial risk for alcoholism by virtue of a paternal family history of alcohol dependence (family history positive: FHP) and a matched comparison group of individuals without a family history of alcohol dependence (family history negative: FHN). In Phase I, Subjects will complete 2 test days, in randomized, balanced order under double blind conditions. Test days will include an IV “clamping” procedure, where subjects will have an infusion of 6% ethanol infusate for approximately 20-25 minutes until target breathalyzer of 100mg/dl is reached, then infusion will continue “clamped” at the breathalyzer target range for an additional 60 minutes OR a placebo infusion, with a similar 20-25 minute run-in infusion and a “clamped” infusion for 60minutes. Phase II: Subjects will complete 2 test days in a randomized, balanced order under double-blind conditions. Test days will involve the 60-minute intravenous bolus + infusion of placebo or bolus of ketamine (0.23mg/kg x 1 minute) followed by a 60-minute infusion of ketamine 0.0097mg/kg/minute (total dose =0.812 mg/kg). Subjects will participate in Phase I first, followed by Phase II, at least 2 weeks apart. All test days within a Phase are conduced at least 3 days apart.
Results
This project has resulted in several publications. One manuscript characterizes behavioral effects of the GABA-A agonist thiopental and ketamine. Both medications produced cognitive and subjective effects similar to ethanol, highlighting the importance of GABA and NMDA receptor systems to the effects of alcohol intoxication. In a related study, the investigators examined the influence of ketamine and thiopental on ERP response during a visual oddball task. Both drugs attenuated neural response, demonstrating the role of GABA and NMDA mechanisms in processing of novel stimuli. Both of these projects provide a framework for understanding the mechanisms by which altered glutamate and GABA receptor systems may affect cognitive functioning and behavioral response to alcohol among FHP individuals.