NIAAA Spectrum NIAAA Spectrum | Volume 2, Issue 1 | February 2010 http://www.spectrum.niaaa.nih.gov In ThIs Issue FeaTures 1 Playing Matchmaker: Finding Personalized Approaches To Solve Alcohol Problems 3 Alcohol and Cancer News PhoTo essay 2 Input, Output, Throughput: How Is High-Throughput Technology Advancing Alcohol Research Problems CharTICle 3 Drinking Too Much Can Kill You Quickly...or Slowly news From The FIeld 4 Molecule Repairs Alcohol Metabolism Enzyme 4 The Vine That Ate the South May Help Alcoholics Curb Cravings 5 Can Drinking During Pregnancy Affect Kids’ Behavior? 6 Can Drinking Policies Keep Risks at Bay? 6 Looking To Sober Up? Caffeine Is Not the Answer 7 Marriage and Parenthood May Protect Against Stress- Induced Harmful Drinking 5 QuesTIons wITh... 7 David Goldman, M.D. W e’ve come to expect so much in our lives to be tailored to our personal preferences—from our music playlists, to our coffee choices, to our exercise workouts. Now, thanks to the concept of personalized medicine, health care options are beginning to follow suit. In the past, researchers developed medical treatments based on studies that determined what proportion of people with a particular disorder responded to various treatments for that disorder. Treatments with the highest proportions of positive responses were deemed best for nearly everyone. However, it has become clear that not every individual with a particular disorder responds to the same treatment in the same way. Much of how people respond has to do with individual genetic makeup, environmental influences, and their complex interactions. Personalized medicine takes these factors into account. As in other areas of medicine, researchers in the alcohol field are taking a personalized approach to understanding, preventing, and treating alcohol-related problems across the lifespan. As NIAAA fosters the development of new and more effective medications for dependence, learning more about which medications work best for whom is an important priority. New research is helping NIAAA to be more strategic about the medications tested, the way they are tested and designed, and how to determine the subpopulations of patients who are most likely to benefit from them. For example, information about an individual’s subtype of alcohol dependence can guide treatment strategies and help predict which medications will be most effective for a given patient. (See “Alcoholism Isn’t What It Used To Be” in NIAAA Spectrum, Vol. 1, Issue 1, September 2009.) Likewise, identifying individual genetic makeup can help predict who may respond positively to a specific medication. For example, sequence variations in genes linked to an increased vulnerability for alcohol dependence such as mu opioid receptor and dopamine D4 receptor have been associated with the efficacy of certain medications. A recent study showed that a particular gene (OPRM1) predicts which patients are likely to respond well to naltrexone, a medication for alcohol dependence. FeaTure Playing MatchMaker: Finding Personalized aPProaches to solve alcohol ProbleMs Researchers in the alcohol field are taking a personalized approach to understanding, preventing, and treating alcohol-related problems across the lifespan.
We’ve come to expect somuch in our lives to betailored to our personal
preferences—from our music playlists,to our coffee choices, to our exerciseworkouts. Now, thanks to the conceptof personalized medicine, health careoptions are beginning to follow suit.In the past, researchers developedmedicaltreatmentsbasedonstudiesthatdetermined what proportion of peoplewith a particular disorder respondedto various treatments for that disorder.Treatmentswiththehighestproportionsofpositiveresponsesweredeemedbestfor nearly everyone. However, it hasbecome clear that not every individualwith a particular disorder responds tothe same treatment in the same way.Much of how people respond has todo with individual genetic makeup,environmental influences, and theircomplexinteractions.
Personalized medicine takes thesefactors into account.As in other areasof medicine, researchers in the alcoholfieldaretakingapersonalizedapproachto understanding, preventing, andtreatingalcohol-relatedproblemsacrossthelifespan.
As NIAAA fosters the development ofnew and more effective medicationsfor dependence, learning more aboutwhichmedicationsworkbestforwhomis an important priority. New researchis helpingNIAAA to bemore strategicabout the medications tested, the waythey are tested and designed, and howto determine the subpopulations ofpatients who aremost likely to benefitfrom them. For example, informationabout an individual’s subtype ofalcoholdependencecanguidetreatmentstrategies and help predict whichmedications will be most effectivefor a given patient. (See “AlcoholismIsn’t What It Used To Be” in NIAAA Spectrum, Vol. 1, Issue 1, September2009.) Likewise, identifying individualgenetic makeup can help predict whomay respond positively to a specificmedication. For example, sequencevariationsingeneslinkedtoanincreasedvulnerability for alcohol dependencesuchasmuopioidreceptoranddopamineD4 receptor have been associated withthe efficacy of certain medications. Arecent study showed that a particulargene (OPRM1) predicts which patientsarelikelytorespondwelltonaltrexone,a medication for alcohol dependence.
FeaTure
Playing MatchMaker: Finding Personalized aPProaches to solve alcohol ProbleMsResearchers in the alcohol field are taking a personalized approach to understanding, preventing, and treating alcohol-related problems across the lifespan.
National Institute on Alcohol Abuse and Alcoholism
Similarly, personalized information canhelp individualize alcohol treatmentgoals from patient to patient. Desiredoutcomes include abstinence forsome and reducing heavy drinking tolow-risk levels for others, depending ontheindividual.
Advances in pinpointing a connectionbetween individual genetic makeup andenvironmental risk factors for alcoholproblems also are contributing to thedevelopmentofmoreeffectivepreventionstrategies. For example, previous studiesshowed that the short allele or form of
the 5-HTTLPR gene, which is found inover 40 percent of people, is associatedwith impulsivity, low self-control, bingedrinking, and substance use. Recently,researchers at the University of Georgiafound that a family-based preventionprogramdesignedtohelpadolescentsavoidsubstanceuseandotherriskybehaviorwasespecially effective for young teens withthis gene variant. Investigatorsmonitoredthe progress of 11-year-olds enrolled in afamily-centeredpreventionprogramcalledStrongAfricanAmericanFamilies(SAAF)over21/2years,alongwithacomparisongroup.Someoftheparticipantscarriedthe
shortallelevariantandsomecarriedthelongallele.SAAFprogramparticipantswiththeshortalleleofthegenewerenomorelikelythan their longallelecounterparts tohavedrunkalcohol,smokedmarijuana,orbeensexually active. They were half as likelyas their short allele counterparts in thecomparisongrouptohaveengagedintheseriskybehaviors.
Using information accumulated fromstudies like these, researchers anddoctors can develop prevention andtreatmentprogramsthatresultinthemostdesirable outcomes. As our capabilitiesexpand,wewill close in on a timewhendeveloping an individualized treatmentplanisasroutineandtargetedascreatingamusicplaylist. .
2
National Institute on Alcohol Abuse and Alcoholism
The“addictionsarray”shownaboveisanexample of high-throughput technologythat enables researchers to study geneslinked with a vulnerability to alcoholdependence, other addictions, mooddisorders,andanxiety.“Weneedtoconductvery large-scaleDNA studies in differentpopulations to understand links betweenvarious genes and alcohol use disordersor other clinical outcomes,” explainsDavidGoldman,M.D., headofNIAAA’sLaboratory ofNeurogenetics. This arrayand other high-throughput technologiesmakethejobfaster,easier,andcheaper.
“Compared to our previous methods, theaddictionsarrayhasallowedustogenerateabout100timesmoredataatone-tenththecost for each data point,” says NIAAA’sColinHodgkinson,Ph.D.,whocoordinatedthe multi-institution team that developedthe array. It is based on a commerciallyavailabledevice,theIlluminaGoldenGatearray, which simultaneously mines theDNA of 96 individuals. The researcherscustomizedthearraytodetectanyof1,350possible variations in 130 genes linkedwithaddictionandtherelateddisordersofanxietyanddepression.Thearrayalsocan
detect186biochemicalmarkersforethnicancestry, a variable that can confoundgeneticstudiesifnotaddressed.
Inanimportantrecentstudy,theaddictionsarrayhelped tovalidateresearchshowingthat a particular gene (OPRM1) predictswhich patients are likely to respondwellto naltrexone, a medication for alcoholdependence. As this type of “personalgenomics” research advances, this arrayand other high-throughput technologieshold great promise for bridging the gapbetween basic research and clinicaltreatmentforalcoholusedisorders. .
PhoTo essay: InPuT, ouTPuT, ThroughPuT: how Is hIgh-ThroughPuT TeChnology advanCIng alCohol researCh?
Articleabstractscanbefoundhere:Addictions Biology: Haplotype-Based Analysis for 130 Candidate Genes on a Single Array. http://www.ncbi.nlm.nih.gov/pubmed/18477577An Evaluation of Mu-Opioid Receptor (OPRM1) as a Predictor of Naltrexone Response in the Treatment of Alcohol Dependence: Results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. http://www.ncbi.nlm.nih.gov/pubmed/18250251
National Institute on Alcohol Abuse and Alcoholism
Excessive alcohol use causes an estimated79,000deathsperyearintheUnitedStates.Most people are unaware that close to halfof these deaths (approximately 36,000annually)resultfromchronicalcohol-relatedillnesses rather than acute causes such asmotorvehiclecrashesandfalls.Unlikeotherdrugs, alcohol disperses in all body tissuesandthereforehasthepotentialtoharmmanyorgan systems. The chart at left shows avariety of conditions linked with drinkingtoomuch,alongwiththeestimatedaveragenumber of alcohol-attributed deaths eachyear.Inthecancercategory,thetopalcohol-related deaths are from cancer of the liver,headandneck,esophagus,andfemalebreast.
CharTICle: drInkIng Too muCh Can kIll you QuICkly . . . or slowly
Source:Alcohol-Attributable Deaths Report, Average for United States 2001-2005, NationalCenterforChronicDiseasePreventionandHealthPromotion,CentersforDiseaseControlandPrevention.
Aninterdisciplinaryworking groupconvened in October 2009 by the International Agency for
Research on Cancer (IARC) concludedthat acetaldehyde associated with alcoholconsumption is a Group 1 carcinogen.TheIARCdefinesGroup1agentsasthosefor which there is sufficient evidencethat they cause cancer in humans. Theworking group also confirmed the Group1 classification of alcohol consumptionand of ethanol in alcoholic beverages.A summary of the group’s assessmentappeared in the November 2009 issue ofThe Lancet Oncology.Acompletewrite-upwillbepublished inanupcomingvolumeofthe IARC Monographs.
Part of the World Health Organization,the IARC brings together expertworkinggroups to evaluate the evidence of thecarcinogenicityofchemicals,occupationalexposures, and lifestyle factors. Alcoholconsumptionislinkedtocancersoftheoralcavity,pharynx,larynx,esophagus,colon,rectum,liver,andfemalebreast.Evidencelinking alcohol to cancer of the pancreasislimited.
When alcohol is consumed, it is firstmetabolizedintoacetaldehyde,achemicalsimilar to formaldehyde, which causesDNA damage and has other cancer-promotingeffects.Aldehydedehydrogenase2(ALDH2)isthemainenzymeresponsiblefor breaking down acetaldehyde into
acetate,anon-toxicmetaboliteinthebody.Many people of EastAsian descent haveaninactivevariantoftheALDH2enzyme.Whenindividualswiththeinactivevariantdrink alcohol, acetaldehyde accumulatesinthebodyandputsthematelevatedriskfor alcohol-related cancer.As pointed outrecently by NIAAA researchers, heavyalcohol consumption greatly increasesthe risk for esophageal cancer amongsuch individuals, and greater awarenessof this risk among affected individualsand their doctors could have importantimplications for cancer prevention. (See“Alcohol‘Flush’SignalsIncreasedCancerRisk”inNIAAA Spectrum,Vol.1,Issue1,September2009.) .
FeaTure
alcohol and cancer newsAlcohol consumption is linked to cancers of the oral cavity, pharynx, larynx, esophagus, colon, rectum, liver, and female breast.
National Institute on Alcohol Abuse and Alcoholism
National Institute on Alcohol Abuse and Alcoholism
Anexperimentalcompoundrepaireda defective alcohol metabolismenzyme that affects an estimated
1 billion people worldwide, according toresearch supported byNIAAA.PublishedJanuary 10, 2010, in the advance onlineeditionofNature Structural and Molecular Biology,thefindingsuggeststhepossibilityof a treatment to reduce health problemsassociatedwiththeenzymedefect.
“We recently identified amolecule calledAlda-1thatactivatesthedefectiveenzyme,and in the current study, we determinedhow this activation is achieved,” said thestudy’s senior author, ThomasD. Hurley,Ph.D., professor and associate chairmanof biochemistry andmolecular biology atIndianaUniversitySchoolofMedicine inIndianapolis.InitialinvestigationsofAlda-1 were led by co-author Daria Mochly-Rosen, Ph.D., professor of chemical andsystems biology at Stanford UniversitySchoolofMedicine.
After alcohol is consumed, it is firstmetabolized into acetaldehyde, a toxicchemical that causes DNA damage.
Aldehyde dehydrogenase 2 (ALDH2) isthemainenzymeresponsibleforbreakingdownacetaldehydeintoacetate,anontoxicmetabolite in the body. It also removesother toxicaldehydes thatcanaccumulateinthebody.
About 40 percent of the East Asianpopulation and many people of EastAsian descent throughout the worldcarry a variant of the ALDH2 gene thatproduces an inactive form of ALDH2.When individuals with this variant drinkalcohol, acetaldehyde accumulates in thebody, resulting in facial flushing, nausea,andrapidheartbeat. Inaddition to its linktoincreasedcancerrisk,theinactiveformofALDH2alsoreducestheeffectivenessofnitroglycerin,adrugusedtotreatangina.
In a series of experiments that examinedthe interaction between Alda-1 and thedefectiveALDH2enzyme,Dr.Hurleyandhis colleagues found thatAlda-1 restoredthe structure of the inactive enzyme.Thenormal, active form ofALDH2 creates acatalytictunnel,aspacewithintheenzymein which acetaldehyde is metabolized,
explained Dr. Hurley. In the defectiveenzyme, the tunnel does not functionproperly. Alda-1 binds to the defectiveenzyme in away that effectively reopensthe catalytic tunnel and thus allows theenzymetometabolizeacetaldehyde.
“The manner in which Alda-1 binds tothe structure ofALDH2 provides uswithpowerful insight into the relationshipsbetween activators and inhibitors of thiscrucial detoxifying enzyme,” says Dr.Hurley. “This insight will lead to themodification of Alda-1 to improve itspotency,andalsoopensup thepossibilityof designing new analogs that canselectively affect themetabolismof othermolecules that aredetoxifiedbyaldehydedehydrogenase.” .
news From The FIeld
Molecule rePairs alcohol MetabolisM enzyMe
news From The FIeld
the vine that ate the south May helP alcoholics curb cravings
The kudzu plant, nicknamed the“vine that ate the South” for itsfast and wild growth throughout
the southeasternUnited States,may help
alcoholicscurbtheirdesiretodrink.Asidefrom being a pesky weed, kudzu is themainingredientinaChinesefolkmedicineused for 1,000 years to treat alcoholism.
A study published in the November2009 issue of Alcoholism: Clinical and Experimental Researchinvestigatedanewcompoundthatworksmuchthesameway
National Institute on Alcohol Abuse and Alcoholism http://www.spectrum.niaaa.nih.gov
Thearticleabstractcanbefoundhere:Alda-1 Is an Agonist and Chemical Chaperone for the Common Human Aldehyde Dehydrogenase 2 Variant. http://www.ncbi.nlm.nih.gov/pubmed/20062057
Daidzin, one of the active ingredients in kudzu, inhibits ALDH2.
A recently identified molecule called Alda-1 activates the defective enzyme.
National Institute on Alcohol Abuse and Alcoholism http://www.spectrum.niaaa.nih.gov
asoneofkudzu’sactiveingredients.Thisinformation may help scientists developnewdrugstocombatalcoholism.
Researchers led by IvanDiamond,M.D.,Ph.D., University of California at SanFrancisco, based their work on twopremisesdemonstratedbypreviousstudies.The first is that people are less likely todrinkheavilyorbecomealcoholicsiftheylackaldehydedehydrogenase2(ALDH2),anenzymethatbreaksdownalcoholinthebody.A deficiency inALDH2 can causea substance called acetaldehyde to buildup. An accumulation of acetaldehydetriggers a “flushing reaction” in drinkers,with symptoms that can include nausea,headaches, and a racing pulse. Anaccumulation of acetaldehyde also alters
themetabolismofdopamine,whichcouldreduce the desire to drink. The secondpremise is that daidzin, oneof the activeingredientsinkudzu,inhibitsALDH2.
Diamond and his team developed asynthetic substance called CVT-10216,modeledafterdaidzin,butdesignedtobeevenmoreeffectiveatinhibitingALDH2.Theytesteditinvariousratmodelsusingavarietyofexperimentalparadigms.Ratswho receivedCVT-10216not onlydrankless,buthadreducedalcoholcravings.
By monitoring the rats’ blood and brainchemistry, the researchers exploredpossible mechanisms that caused thesecravings to wane. One possibility is theeffect on the dopamine system. During
alcohol intake, CVT-10216 preventsincreased levels of dopamine fromaccumulating in the nucleus accumbens,anareaofthebrainthatperceivesdrinkinginpositiveorrewardterms.Stabilizingthisbrain chemistrymay be the key toCVT-10216’sinnovativepotential.
Since alcohol-dependent rats can modelsome of the addictive behaviors seenin humans, this new research may helpdevelopnewdrugstotreattherootcausesofaddictionandrelapse. .
Thearticleabstractcanbefoundhere:Suppression of Heavy Drinking and Alcohol Seeking by a Selective ALDH-2 Inhibitor.http://www.ncbi.nlm.nih.gov/pubmed/19673742
the vine that ate the south May helP alcoholics curb cravings, contnued
Research points to a possible linkbetweendrinkingduringpregnancy and behavioral problems in
children. Australia-based researcherspolledarandomsampleofmorethan2,000mothersat3monthspost-partumon theirpregnancy drinking habits. By followingupwiththesesamemothersafter2,5,and8years had elapsed, the researcherswereabletogatherdataonthebehavioraltrendsintheirchildren.
AccordingtotheanalysispublishedintheJanuary2010 issueofAddiction, childrenwhose mothers drank moderate to heavyamountsofalcoholduringearlypregnancysuffered from anxiety, depression, andinexplicableachesandpainsathigherratesthanchildrenwhosemothersdranklittleto
noalcoholwhilepregnant.Childrenwhosemothersdrankmoderatetoheavyamountsofalcoholinthesecondandthirdtrimesterswere more likely to exhibit aggressivebehavior than children whose mothersdranklessorabstained.Astheamountandfrequency of drinking increased, the riskforbehaviorproblemsinthechildrenwentup as well. The study defines moderatedrinkingbymothersasthreetofourdrinksper occasion, and up to seven drinksperweek.
These results support thenotion that fetaldevelopment is vulnerable to alcoholexposurethroughoutpregnancy.That’swhypregnantwomengenerallyarecautionedtoabstainfromalcoholcompletely.
According to the study’s lead author,ColleenO’Leary,M.P.H., of theTelethonInstitute for Child Health Research,alcohol’s unpredictable risks are reasonenoughforextracaution.“Noteverysmokergets lung cancer despite being at higherrisk—andinthiscase,noteverychildwillbeaffectedbyprenatalexposuretoalcohol.However,itisimportantthatwomenhavethis information about increased risk sothat they canmake informeddecisions togivetheirchildthebeststarttolife.” .
news From The FIeld
can drinking during Pregnancy aFFect kids ehavior’ b ?
Australia-based research supports the notion that fetal development is vulnerable to alcohol exposure throughout pregnancy.
Thearticleabstractcanbefoundhere:Evidence of a Complex Association Between Dose, Pattern and Timing of Prenatal Alcohol Exposure and Child Behaviour Problems. http://www.ncbi.nlm.nih.gov/pubmed/19922516
Neighborhoodswheremanyalcohol-selling establishments operatein close proximity to each other
tendtohavehigherincidencesofalcohol-related violence and aggressive behavior.In collaboration with the Task Force onCommunityPreventiveServices,scientistsat the Centers for Disease Control andPrevention and other experts in research,practice, and policy worked togetherto select and review recent researchaddressing this topic. Their findings,publishedintheDecember2009issueofthe American Journal of Preventive Medicine,suggest that effective policies limitinghow many alcohol outlets can exist in agiven area may help reduce thesealcohol-relatedproblems.
Public health benefits may be foundin limiting the concentration of both“on-premises” outlets where alcohol isconsumed where purchased and “off-premises” outlets where alcohol ispurchased for consumption elsewhere,such as at home.The researchers explainthat people tend to congregate in areaswheretherearemanyplacestobuyalcoholand consume it on-premises, like bars,restaurants, and ballparks. When thesepeopledrinkexcessively,theymaybecomeaggressiveorviolent.Withrespect tooff-premises outlets, like convenience stores,grocery stores, and liquor shops, ahigherdensity of outletsmay increase excessiveconsumption by decreasing the effortneededtogetalcohol.
The authors conclude that reducing thenumber of alcohol-selling outlets ina given community can make alcoholharder to access and perhaps moreexpensive, thereby reducing adversealcohol-relatedconsequenceslikeviolenceandaggression..
news From The FIeld
can drinking Policies keeP risks at bay?Public health benefits may be found in limiting the concentration of both “on-premises” and “off-premises” alcohol outlets.
news From The FIeld
looking to sober uP? caFFeine is Not the answer
Drinking caffeine to combat alcohol’s numbing effect on thinking and judgment actually leaves drinkers even more open to risky behavior.
The conventional wisdom that astrongcupofcoffeecansoberyouupaftertoomuchdrinkingisabout
Researchers from Temple Universityadministered caffeine and alcohol—separately in some experiments, togetherinothers—tolabmice.Themicereceivedenough alcohol to inebriate them. Theyalso received the caffeine equivalent ofonetoeightcupsofcoffee.Theresearcherstested the mice’s changes in anxiety
levels (as indicated by howmuch time amouse spent in theopenareaofamaze),movement,andabilitytolearnwhileunderthe influence of various combinations ofthetwosubstances.
Mice that received alcohol alone ranaround more, but felt less anxious andhadmore difficulty learning than controlmice. Mice that received just caffeinefeltmoreanxious,butmovedandlearnedmorepoorlythancontrolmice.Whenmice
National Institute on Alcohol Abuse and Alcoholism http://www.spectrum.niaaa.nih.gov
All evidence points to serious risks associated withcaffeine–alcohol combinations.
Thearticleabstractcanbefoundhere:The Effectiveness of Limiting Alcohol Outlet Density as a Means of Reducing Excessive Alcohol Consumption and Alcohol-Related Harms. http://www.ncbi.nlm.nih.gov/pubmed/19944925
National Institute on Alcohol Abuse and Alcoholism http://www.spectrum.niaaa.nih.gov
Stress is a known risk factor forharmfuldrinking,andthatincludesstressresultingfromterroristattacks
and terrorism-related fears. However,terrorism-relatedstressmaybelesslikelyto cause harmful drinking in individualswho are married or have children. Thisfinding was published in the December2009issueofThe Journal of Nervous and Mental Disease.
Researchersstudiedtheeffectsofterrorism-relatedstressondrinkingbehaviorsusinga long-term survey that began in 1996.Survey respondents were initially drawnfrom 2,492 employees at a midwesternuniversity andwere surveyed before andafterthe9/11terroristattack.Respondentsestimatedtheirnumberofalcoholicdrinksper day and their frequency of drinkingforescapism,drinkingtointoxication,andbingedrinking.
Married individualswere less likely thanunmarried individuals to have terrorism-related stress lead to harmful drinkingbehaviors, such as frequently drinkingto intoxication and binge drinking.Individualswithchildrenshowedasimilarprotective effect against terrorism-relatedstresspromptingdrinkingtointoxication.However, this protective effect againstterrorism-related stress leading to bingedrinking was found only in men withchildren; women with children were notless likely than women without childrento binge drink due to terrorism-relatedstress..
news From The FIeld
Marriage and Parenthood May Protect against stress-induced harMFul drinking
Terrorism-related stress may be less likely to cause harmful drinking in individuals who are married or have children.
receivedbothalcoholandcaffeinetogether,they were less anxious but had the samedifficulty learning as mice that receivedalcoholalone.Asaresult,thesemicewerestillunabletododgewhattheyknewweredangerousareasofamaze.
ThomasGould, Ph.D., who co-conductedtheresearchpublishedintheDecember2009issueofBehavioral Neuroscience,believesthe results have broad implications forhumanalcoholandcaffeineconsumption.
Theresearchersconcludedthatconsumingcaffeine and alcohol together may makea drunken person feelmore alert, but thecombinationwillnotmakethepersonanylessimpaired.Infact,theeffectisquitetheopposite.Asaresult,drinkerswhowronglybelievetheycanoffsettheeffectsofalcoholwith caffeinemake poor decisions.Thesearetheverydecisionsthatleadtoproblemssuchasdrunkdrivinganddrinkingenoughtorequiremedicalcare.
“The bottom line is that, despite theappeal of being able to stay up all nightand drink, all evidence points to seriousrisks associated with caffeine–alcoholcombinations,”saidDr.Gould. .
Thearticleabstractcanbefoundhere:Effects of Ethanol and Caffeine on Behavior in C56BL/6 Mice in the Plus-Maze Discriminative Avoidance Task. http://www.ncbi.nlm.nih.gov/pubmed/20001110
Thearticleabstractcanbefoundhere:Terrorism, Distress, and Drinking: Vulnerability and Protective Factors. http://www.ncbi.nlm.nih.gov/pubmed/20010027
1. Wehearagreatdealaboutgeneticsin many areas of health research.Whyisthisfieldsoimportantforthestudyofalcoholusedisorders?
Genetics research is critical to ourunderstanding of the most fundamentalquestions about alcoholism—who among
our family, friends, and neighbors aremost susceptible to developing alcoholproblems,andhowcanwehelpthem?
We’vemadeenormousstridesinidentifyingthe traits that signal a predisposition toalcoholism, which can help us interveneearlier—andmoreeffectively.
Perhapsmoreimportant,geneticsresearchhas shown that it is not always a simplepath, so we need to learn how geneticsarelinkedtoaddictionsinbothdirectandindirectways.Somegenes,forexample,aredirectlyrelatedtohowthebodymetabolizesalcoholand thedegree towhichdrinkers’endorphin levels rise. Others are related
5 QuesTIons wITh...
david goldMan, M.d., chieF oF niaaa’s laboratory oF neurogenetics
indirect ly—throughstress,anxiety, andp e r s on a l i t ydisorders, fore x a m p l e—which oftenleadpeople toself-medicatet h r o u g ha l c o h o l .Some genesare related
to general risk-taking behaviors, whichare also linked to alcohol use disorders.And somegenes even serve as protectivefactors, particularly among thosewhoarehighlysensitivetothenauseaanddizzinessthatcanaccompanydrinking.
Learning more about the complexrelationships among all these geneticfactors—andtheenvironmentaleffectsthattrigger them—isessential tofindingwaystohelp themillionsofpeopleaffectedbyalcoholusedisorders.
2. In a 1989 interview, you discussedyourwork,atthetime,ofidentifyingbiomarkersforalcoholism,withtheeventualgoalofidentifyingthegenesthat produce them. Looking back20yearslater,areyousatisfiedwithhowthefieldhasprogressed?
Yes,I’msatisfiedtoadegree.Asascientist,you alwayswant the rate of discovery tobe faster than it is, but I do think we’vemade a number of important advances inseveralareas.
First, early studies of biomarkers—including alcohol-induced flushing,alcohol response, and brain imagingresponses—have led to current studies ofthe genes themselves.This type of study,conducted on what is sometimes calledan intermediatephenotype,haspointed toroles of genes in particular mechanisms,suchasstressresponse,thatareimportantin alcoholism,other addictions, andotherpsychiatricdisorders.
Second,thestudiesinanimalmodelshaveledtoadvancesinthebasisofalcoholisminhumans, particularly in gene-environmentinteractionstudieswhere it ispowerful tobeabletocontroltheenvironment.
Andfinally, on an overall basis,we havelearned the importance of several genesthat determine stress resilience or whoseeffects are modified by stress, and eventhat endocrine context matters. ThosegenesincludeneuropeptideY,theserotonintransporter,andmonoamineoxidaseA.
Because of these developments, I believewehaveamuchbetterhandlenowonwhatwe know about the human genome andwhereweneedtogoinordertobuilduponthatknowledge.Ialsothinkwe’vehelpedreachapointwheregenetics researchcanhelp inform clinical work, which is, ofcourse,theultimategoalofourinvestment.
3. What are some specific ways thatgenetics research can help in thepreventionandtreatmentofalcoholusedisorders?
Genetics research has raised awarenessthat the main reason alcoholism runs infamiliesisgeneticpredisposition.Allofusare at some risk for alcoholismandotheraddictions, but awareness of familial riskcanbevaluabletopeoplewho,becauseoftheir familyhistory,areathigher riskbutwho want to avoid problems they havewitnessedintheirrelatives.
Clearly, we are a long way from havingsufficient geneticmarkers towarn peopleofrisk,andalsoitislikelythattheuseofsuch markers would be complicated, forexample,by theneedtounderstandgene-environment interactions. One preventiontoolatourdisposal is theknowledge that500 million people worldwide carry adeficiencyof thealdehydedehydrogenasegene. These individuals flush afterdrinking and have a higher risk of uppergastrointestinalcancers;however,theycanpreventmostofthosecancersbyreducing,orstopping,theirconsumptionofalcohol.
With regard to treatment, genetics givesus the key to match the best therapeuticplan with the best candidate. In thepast, clinicians have had to rely, to somedegree, on trial and error in applyingpharmacological and psychologicalinterventions.Now,weknowagreatdealmore about which medicines are likelyto work for which patients—based ongeneticsprofiles.
Take the drug naltrexone, for example.For many patients, it’s not particularlyeffective.However,ratherthanabandoningits use, ongoing research is showing thatthis drug, which is used in combinationwithpsychotherapy, isveryeffectivewithalcoholics who have a particular geneticvariation in one of their opioid receptors.So it is highly effective with roughly aquarterofallpatientsintreatment.
Breakthroughs like this are helping uslearnhow tomatch specific treatments toapatient’sgenotype—savingtime,money,and—ultimately—familiesandlives.
4. Whilegeneticsresearchisconstantlyevolving, are there any newdevelopmentsinthefieldthatyou’reparticularlyexcitedabout?
Yes: our work in imaging genetics isparticularlyuseful.Thishashadtheeffectoftyinggeneticvariationmuchmoredirectlytotheprocessesthegenesarealtering—forexample, theeffectofstress-relatedgeneson brain stress responses. A genomicstechnology that is very important is thenewabilitytosievethegenomewitharraysof a million (or more) genetic markers,which recently led to the identificationofageneinvolvedinnicotineaddiction.Andalcoholicsoftensmoke,sotheconnectionsarebecomingclearer.
Looking ahead 5 to 10 years, we expectthat we will learn even more about thecomplexities of the human genome,particularlyasitrelatestoalcohol.Oneareathat seems particularly promising is deepsequencing—aprocessforuncoveringrareanduncommonvariants.Mostofthegene
National Institute on Alcohol Abuse and Alcoholism http://www.spectrum.niaaa.nih.gov
National Institute on Alcohol Abuse and Alcoholism
abouT usNIAAA Spectrum is NIAAA’s first-everwebzine. With engaging feature articles,shortnewsupdates,andcolorfulgraphics,NIAAA Spectrum offers accessible andrelevant information on NIAAA and thealcohol researchfield forawide rangeofaudiences. Each issue includes feature-length stories, news updates from thefield, charticles and photo essays, and aninterview with an NIAAA staff memberor alcohol researcher.NIAAA Spectrum ispublishedthreetimesayear.
I suspect Iwouldstillbeascientist, inwhichcase IwouldbesomewhereelseatNIH,which is probably the best place in theworld for a scientist towork.However,beforeIwasaresearcherIwasaphysician.Onaday-to-daybasistherewas nothing that I have ever done that wasmore rewarding, challenging, andoccasionallyheart-wrenchingthanhelpingmypatientsandtheirfamilies..
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If you enjoy the NIAAA Spectrum, visit http://www.niaaa.nih.gov for other NIAAA alcohol research and education products.
Number 78 Ju ly
A DEVELOPMENTAL PERSPECTIVE ON UNDERAGE ALCOHOL USE
Dramatic developmental changes unfold as individuals mature from birth to childhood, from childhood to adolescence, and from adolescence to early adulthood. These include physiological changes—such as physical growth, brain development, and puberty—as well as psychological and social changes—such as an evolving sense of self, forming
and school settings, undergoing puberty, gaining grindependence, and taking on more responsibilities. milestones may come earlier for some individuals thdepending on how quickly they mature, but tend tospond, in general, to certain ages and developmenta
• Prenatal: prior to birth • Ages 0–10: childhood • Ages 10–15: early to midadolescence • Ages 16–20: late adolescence • Ages 21–25: transition to early adulthood
2009
more mature relationships with friends, and transitioning from middle school to high school.
Developmental changes factor into underage drinking. For example, as a high school student transitions to college, he or she may experience greater freedom and autonomy, creating more opportunities to use alcohol. Underage drinking also can influence development, potentially affecting the course of a person’s life. For example, alcohol use can interfere with school performance and/or negatively affect peer relationships.
This Alcohol Alert examines the complex relationship between underage drinking and development: how developmental factors influence drinking, the social and physical consequences of alcohol use, and how various developmental stages can be specifically targeted to design more effective measures for preventing or treating underage drinking.
Key Stages in Human Development As children mature, they achieve key developmental milestones such as changing the way they relate to parents and peers, beginning school and moving through different grades
“Chronic heavy drinking during adolescence has been linked to cognitive deficits and alterations in brain activity and structure.”
eater These an others, correl stages:
Each stage in development carries risks for alcohol use and its consequences. Studies show that alcohol use typically begins in early adolescence (ages 12–14) (1) and that between ages 12 and 21, rates of alcohol use and binge drinking1 increase sharply before leveling off in the twenties (see figure, page 3) (2).
How Developmental Factors Influence Drinking and Risk for Drinking Researchers are investigating the complex relationship between developmental factors and alcohol use to better understand how the risks for drinking and alcoholrelated problems emerge across development.
Personality and Behavior. Aspects of personality/temperament and certain behaviors that are evident early in life—often before children enter elementary school—such as antisocial behavior, poor selfregulation, poor selfcontrol, anxiety, a tendency toward depression, and shyness may predict initiation of alcohol use in early adolescence, as well as future heavy use and alcohol use disorders (AUDs) (3,4). Individuals with the most persistent personality and behavior problems are
those most likely to experience more chronic and severe forms of AUDs in adulthood (5).
Family Dynamics. Family dynamics also factor into a child’s risk for underage drinking. When parents respond well to their child’s needs, 1 Binge drinking is defined as consuming five or more drinks in a row for men and four or more drinks in a row for women. Source:http://www.collegedrinkingprevention.gov.
U.S. Department of Health& Human Services National Institutes of Health
National Institute on Alcohol Abuse and Alcoholism
Alcohol Alert (http://www.niaaa.nih.gov/Publications/AlcoholAlerts) is NIAAA’Squarterly bulletin that disseminates importantresearch findings on a single aspect of alcoholabuseandalcoholism.
Alcohol Research & Health (http://www.niaaa.nih.gov/Publications/AlcoholResearch)is NIAAA’s quarterly, peer-reviewed scientificjournal.
RethinkingDrinking(http://rethinkingdrinking.niaaa.nih.gov) is NIAAA’s newest resourceswhere individuals can evaluate their owndrinkingpatterns.
College Drinking—Changing the Culture(http://www.CollegeDrinkingPrevention.gov),created by NIAAA, is your one-stop resourcefor comprehensive research-based informationon issues related to alcohol abuse and bingedrinkingamongcollegestudents.
National Institute on Alcohol Abuse and Alcoholism
