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Pharmacogenomics Review For reprint orders, please contact: [email protected] Pharmacogenomics 16 Review 2015/04/30 Subjective response as a consideration in the pharmacogenetics of alcoholism treatment Pharmacogenomics Currently available pharmacological treatments for alcoholism have modest efficacy Daniel JO Roche1 and high individual variability in treatment outcomes, both of which have been partially & Lara A Ray*,1 attributed to genetic factors. One path to reducing the variability and improving the 1Department of Psychology, University of California, 1285 Franz Hall, Box 951563, efficacy associated with these pharmacotherapies may be to identify overlapping Los Angeles, CA 90095-1563, USA genetic contributions to individual differences in both subjective responses to alcohol *Author for correspondence: and alcoholism pharmacotherapy outcomes. As acute subjective response to alcohol Tel.: +1 310 794 5383 is highly predictive of future alcohol related problems, identifying such shared Fax: +1 310 206 5895 genetic mechanisms may inform the development of personalized treatments that [email protected] can effectively target converging pathophysiological mechanisms that convey risk for alcoholism. The focus of this review is to revisit the association between subjective response to alcohol and the etiology of alcoholism while also describing genetic contributions to this relationship, discuss potential pharmacogenetic approaches to target subjective response to alcohol in order to improve the treatment of alcoholism and examine conceptual and methodological issues associated with these topics, and outline future approaches to overcome these challenges. Keywords: 5-HT3 • 5-HTT • alcohol • alcoholism • GABAA • naltrexone • OPRM1 • pharmacogenetics • pharmacotherapy • subjective response Overview surable and aversive effects [7], which over Alcoholism is a complex psychiatric disorder the course of repeated alcohol exposure will marked by the interplay between genetic and function as a determinant of future alcohol environmental risk factors [1] . A multitude of intake and related alcoholism risk. neurobiological and psychosocial pathways The degree to which an individual experi- 7 may lead to the outcome of heavy drinking, ences the stimulant and sedative acute effects which may in turn result in the develop- of alcohol across the BAC curve may sepa- ment of alcoholism. These intraindividual rately index future alcoholism risk. Individu- risk pathways include impulsive decision- als that demonstrate greater sensitivity to the 2015 making, externalizing psychopathology, and stimulatory and rewarding effects (e.g., plea- motivation to alleviate negative mood and/or surable/hedonic effects) of alcohol during the anxiety symptoms. Another risk pathway for rising BAC limb are more likely to partici- alcoholism is indexed by the acute subjective pate in binge drinking behavior and develop response to alcohol (SR) [2]. The subjective alcohol-related problems [3,8]. Furthermore, effects of alcohol involve both stimulant and individuals who are less sensitive to the sedative properties with the former being aversive effects of alcohol (i.e., sedative and more prominent during the ascending limb unpleasant effects), particularly during the of the blood alcohol concentration (BAC) declining BAC limb, are also more likely to curve and the latter being most salient dur- develop alcoholism [9–11] . Because SR repre- ing the descending limb [3–6]. Therefore, SR sents a fairly discrete pathway of vulnerability represents the interplay between both plea- to alcoholism, drugs that affect SR, either by part of 10.2217/PGS.14.143 © 2015 Future Medicine Ltd Pharmacogenomics (2015) 16(7), 721–736 ISSN 1462-2416 721 Review Roche & Ray attenuating alcohol’s rewarding effects or increasing its and unpleasant effects of alcohol, or reduced stimula- aversive effects, have been targeted during medication tion and reinforcement, are associated with decreased development for alcoholism [2,12]. alcohol use and preference [21,22]. Currently approved pharmacological treatments Schuckit and colleagues produced much of the early for alcoholism in the USA have modest efficacy and seminal work on both the assessment of SR during labo- high individual variability in treatment outcomes, ratory alcohol administration sessions and how SR may both of which have been partially attributed to genetic relate to future alcohol-related problems [23,24]. In these factors [13–17] . One path to reducing this variabil- studies, the primary measure of SR was the Subjective ity and improving the efficacy associated with these High Assessment Scale (SHAS), which consists of pharmaco therapies may be to identify shared genetic various positive and negative mood-related adjectives, contributions to individual differences in both SR and as well as a single item ad hoc scale of ‘feeling high.’ alcoholism pharmacotherapy outcomes. Doing so may Principal components analysis of the SHAS suggested inform the development of personalized treatments that the ‘maximum terrible feelings’ construct loaded that can effectively target converging pathophysiologi- into a first factor and accounted for 46% of the total cal mechanisms that convey risk for alcoholism. To variance [25,26], thereby suggesting that the SHAS may that end, the objective of this review is threefold. First, be most sensitive to the aversive effects of alcohol. In it will review the well-established relationship between support, a factor analysis found that the SHAS is most SR and the etiology of alcoholism, while also outlining strongly correlated with measures of alcohol-induced recent findings of genetic associations to SR. Second, it sedation [7]. A longitudinal study of sons of alcohol will discuss potential pharmacogenetic approaches to dependent probands and controls indicated that indi- target SR in order to improve the treatment of alcohol- viduals who reported reduced sedative or aversive SR ism. Finally, it will examine conceptual and method- in the laboratory (measured by the SHAS) were more ological issues associated with pharmacogenetic con- likely to develop alcoholism at follow-up [10] . While siderations in the treatment of alcoholism and outline this is compelling evidence that SR predicts future future approaches to overcome these challenges. alcohol-related problems, it is currently unclear how a reduced SR actually translates to real-world drink- Subjective response to alcohol & alcoholism ing behavior and conveys future alcoholism risk. It has etiology been hypothesized that experiencing a reduced SR will The acute pharmacological and subjective effects of lead to excessive alcohol consumption because these alcohol are biphasic in nature [4,6,18]. Pharmacological individuals will need to drink more to experience the effects refer to the cellular and physiological effects of effects of alcohol (Low Level of Response Model) [27], alcohol while subjective effects describe an individual’s but as discussed by others [28,29] this theory remains self-reported perceptions of the substance’s pharmaco- untested. logical effects. It has been well documented that when An important effort toward resolving discrepancies BAC is rising or reaches a stable peak, alcohol pro- in the alcohol administration literature comes from duces robust stimulatory and pleasurable subjective the work of Newlin and Thomson [25]. In the context effects [3,5]. Conversely, alcohol’s subjective effects are of their review of alcohol challenge studies of sons of largely sedative and unpleasant as BAC declines [7]. alcohol dependent parents and controls, they proposed While this pattern of SR has been well characterized the Differentiator Model for understanding psycho- across studies, individuals widely vary in their subjec- biological responses to alcohol as a function of fam- tive experience of the pharmacological effects of alco- ily history of alcoholism. This model proposes that hol: some individuals may be more or less sensitive to responses to alcohol may be accentuated during rising the rewarding and stimulant effects of alcohol, while BAC (i.e., acute sensitization) and attenuated during others report variable sensitivity to alcohol’s aversive falling BAC (i.e., acute tolerance). The authors pro- and sedative effects. Alcohol administration stud- pose that sons of alcohol dependent individuals may ies have documented this variability in SR and have be at risk for alcoholism because they display both shown that these differences may play a significant role heightened sensitivity to the rewarding effects of alco- in predicting the frequency and quantity of alcohol use, hol during the rising limb of the BAC and reduced as well as future alcoholism risk. When SR is divided sensitivity to the unpleasant effects of alcohol as BAC into stimulant/rewarding and sedative/aversive effects, declines. Acute tolerance and acute sensitization occur laboratory studies demonstrated that greater alcohol- within session and represent a useful way to capture induced stimulation and reward is associated with the ‘snap shot’ of alcohol’s effects obtained in a single increased alcohol preference and consumption [19,20], administration session. As most of the earlier studies whereas greater subjective experiences of the sedative by Schuckit and colleagues did not measure stimula- 722 Pharmacogenomics (2015) 16(7) future science group Subjective response as a consideration in the pharmacogenetics of alcoholism treatment Review tory responses to alcohol,
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