Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking

Abstract

Background Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk, and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. Methods 132 non-dependent moderate to heavy drinkers, aged 21–27, participated in 2 single-blind, counterbalanced sessions, approximately one week apart. One session was an intravenous alcohol “clamp”, during which breath alcohol concentration was held steady at 60 mg/dL (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of intoxication, enjoyment, stimulation, relaxation, anxiety, tiredness and estimated number of drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject’s acute adaptation to alcohol was calculated for each of the 7 subjective measures, and used in a principal component analysis to create a single aggregate estimate for each subject’s adaptive response to alcohol. Analysis of covariance tested if GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype x recent drinking history interaction significantly predicted the adaptive response. Results Recent drinking history (p=0.01), and recent drinking history x genotype interaction (p=0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. Conclusion Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.

Comparison of Subjective Responses to Oral and Intravenous Alcohol Administration Under Similar Systemic Exposures

“…We used the Drug Effects Questionnaire (Gilman et al., ; de Wit and McCracken, ) modified to add the item INTOXICATION (Gilman et al., ), to assess HIGH and INTOXICATION via visual analog scales consistent with our prior published work (Kosobud et al., ). We employed the Biphasic Alcohol Effects Scale (Martin et al., ) to assess SEDATION and STIMULATION.…”

“…Our laboratory's use of the IV route of administration began with the BrAC clamp (O'Connor et al., , ; Ramchandani et al., 1999a), a paradigm in which each individual's BrAC is held constant at the same predetermined level for a prescribed interval, usually hours. Using such methodology, we have explored the relationship between biological family history (Morzorati et al., ; Ramchandani et al., 1999b, ), genetic influence (Kosobud et al., ; Ramchandani et al., ), recent drinking history (Gilman et al., ; Ramchandani et al., ), sensitivity to the limb and rate of change of alcohol exposure (Wetherill et al., ), and other risk factors (Gowin et al., ), to subjective and physiological responses to alcohol.…”

Polymorphism study of nine SNPs associated with subjective response to alcohol in Chinese Han, Hui, Tibetan, Mongolian and Uygur populations

“…Given the large number of neurotransmitter systems potentially involved in alcohol's subjective effects, numerous studies have focused on variants in opioidergic genes, GABAergic genes, serotonergic genes, etc. Among them, the GABAA α2 receptor subunit gene ( GABRA2 ) [ 15 , 16 ], μ-opioid receptor gene ( OPRM1 ) [ 17 , 18 ], serotonin transporter gene ( SLC6A4 ) [ 19 , 20 ] and nicotinic acetylcholine receptors ( CHRNA5–CHRNA3–CHRNB4 gene cluster) [ 21 ] are found to be potentially associated with SR to alcohol.…”

Revisión sistemática de modelos neurobiológicos y ejecutivos en alcoholismo

“…Al hacer la revisión de los artículos originales fundamentados en el enfoque de secuelas, se ha encontrado que varios de ellos son realizados fundamentalmente con muestras de adultos (p. e. Fortier, et al, 2014;Gorini, Roberts, & Mayfield, 2013;Heberlein, et al, 2014;Kosobud, et al, 2015), sin conocer antecedentes premórbidos al inicio de consumo de alcohol y basados en medidas generales (López-Caneda, et al, 2014;Stavro, Pelletier, & Potvin, 2013;Winward, Hanson, Bekman, Tapert, & Brown, 2014). Estos factores podrían estar relacionados con sesgos en la interpretación, y desconocimiento de lo correspondiente a un posible agravamiento de los procesos cognitivos en el alcoholismo, de lo previamente comprometido antes de su inicio.…”