Journal of Studieson Alcohol, Vol. 52, No. 6, 1991

SubjectiveFeelingsand Changesin Body SwayFollowing Diazepam in Sonsof Alcoholicsand Control Subjects* MARCA. SCHUCKIT, M.D.* LORIA. DUTHIE,^.s. * HEIKEI.M. MAHLER,PH.D.* MICHAELIRWIN, M.D. ^NDMARISTELA G. MONTEIRO, M.D., PH.D.* AlcoholResearchCenter,Veterans AffairsMedicalCenter,3350 La Jolla VillageDrive, SanDiego, California92161

ABSTRACT.The possible generalization to diazepamof the dampenedresponse to ethanolin sonsof alcoholic fatherswasevaluated in 62 sonsof alcoholics (familyhistorypositive[FHP] subjects) and62 familyhistorynegative(FHN) controls (124 men).Followingchal-

lengeswith placebo,. 12 and .2 mg/kgof diazepamin threeseparate sessions, evaluationof subjective feelingsandincreases in bodysway revealedno decreasedreactionfor FHPs. (J. Stud. Alcohol 52: 601608, 1991)

ONSANDDAUGHTERS ofalcoholics, themselves at

four-foldincreasedrisk for the future developmentof alcoholism(Schuckit,1987;Goodwin, 1985), demonstrate a decreasedintensity of reaction to ethanol (Schuckit, 1988; Schuckitand Gold, 1988). Thesefindingsindicate

lessresponsiveness in a wide rangeof biologicalsystems impactingon subjectivefeelingsof intoxication,postdrinkingincreases in bodyswayand lessintenseor more evanescent changesin severalneurophysiological measures (Ehlers and Schuckit, 1988; Erwin, 1987; Lex et al., 1988; O'Malley and Maisto, 1985; Pollocket al., 1986; Savoie et al., 1988; Schuckit, 1985; Schuckit et al., 1988). Fur-

ther underscoringthe proteannature of the phenomenon is the documentation

of less intense alcohol-related

alter-

ations in family history positive (FHP) men for three hormonesknownto changeafter appropriatedosesof bev-

eragealcohol,includingcortisol,prolactinandadrenocorticotropin(ACTH) hormones(Schuckitet al., 1987a,b; 1988b).

The prognostic importance of the decreased reactionto alcohol is being evaluatedfurther through an ongoing follow-upof the morethan400 men testedin our laboratory since1978. Pendingthe outcomeof the study,the

Received: December 7, 1989. Revision: March 17, 1990.

*This work was supportedby the VeteransAffairs ResearchService and National Instituteon Alcohol Abuse and Alcoholismgrant05526. *Marc A. Schuckit and Michael Irwin are also affiliated with the Departmentof Psychiatry,Schoolof Medicine, Universityof California, San Diego. Lori A. Duthie and Heike I.M. Mahler are affiliatedexclusivelywith the Departmentof Psychiatry,Schoolof Medicine,University of California, San Diego. Maristela G. Monteiro is with the Departmentof Psychopharmacology, EscolaPaulistade Medicina,S5o Paulo, Brazil.

601

relative consistencyof the findingsover the yearsmakes the decreasedreaction to alcohol a promisingpotential "marker" of alcoholismrisk. However, documentinga dampenedethanolresponsein sucha wide array of evaluationsdoeslittle to pinpointany specificbiologicalsystems as a key mediator of the phenomenon.Useful informationon the possiblemechanismscontributingto the differentialethanolresponsemight resultfrom a determinationof whethera similardecreasedresponsein FHP men is also observedfor otherdrugs. Reflectingour advancedlevel of knowledgeaboutthe clinical effectsand biologicalmechanismsinvolvedwith benzodiazepines, one logical comparisonagentwould be diazepam,a drug for which humanchallengeshave frequentlybeencarried out. Determiningthe level of generalizabilityof the findingto diazepamcan beginto indicate if pharmacological effectssharedby benzodiazepines and ethanolare more or lesslikely to play a centralrole in the diminishedethanolresponse.The lack of a similar dampened responseto diazepammight also indicate whether general psychologicalset or the laboratory atmosphere contributedgreatlyto the data. This study describesthe resultsfrom an evaluationof 62 FHP/FHN pairs (124 men) who were challengedwith two differentdosesof diazepamand with placebo.The specificbenzodiazepinewas chosenbecauseof the availability of good clinical data indicatingappropriatedoses to use and the acceptablelevels of safety for the challenges.The report focuseson the changesin subjective feelingsof intoxicationand levels of body sway after diazepam,and complementsa parallel study on the subset of 74 of these individualsfor whom hormonal changes followinga benzodiazepine challengehavebeenevaluated (Schuckitet al., in press).

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Method

in other

studies in which

1991

veins in the nondominant arm, with one to be used for the

The 124 men tested in this project were selected throughprocedures similarto thoseusedin our laboratory overthe years(Schuckit,1987;SchuckitandGold, 1988). As outlined

/ NOVEMBER

subsets of the

present124 subjectswere included(Anthenelliet al., in press;Monteiroet al., 1990;Schuckitet al., 1991;Schuckit et al., in press),men were first identifiedthrougha questionnaire mailedto all malestudents andnonacademic staff aged 18 to 25 at the Universityof California,San Diego (UCSD) and affiliatedhospitals.The questionnaire was usedto excludeindividualswho alreadydemonstrated severealcoholor drug relatedproblems(lessthan 3%), as well as those who were total abstainers from alcohol and

thosewho had a historyof medicaldisordersor psychiatric problemsthat wouldinterferewith the challengeor its interpretation.All diagnosesfor subjectsand their firstdegreerelativeswerebasedon the criteriaof the DSM-III (American PsychiatricAssociation,1980) as reviewedby a psychiatrist.The FHP subjectsindicatedthat their biologicalfatherfulfilled the criteriafor alcoholabuseor dependenceoutlinedin the instrument,while their mother did not. Each higherrisk subjectwas similarto a family historynegative(FHN) controlon age, race, sex,religion, educationallevel, smokinghistory,drinkinghistory,drug

usehistoryand height-to-weight ratio. Followingthe initial selection,the personaland family historieswere corroborated through a telephone interview, blood tests evaluatingstatemarkersof heavydrinking(e.g., gamma glutamyltransferase) andtheMichiganAlcoholismScreening Test(Selzer, 1971;seealsoSchuckitand Irwin, 1988). No subjectnor any close family memberwas known to have met criteria for benzodiazepine abuseor dependence. After the initial evaluation,thesedrinkingbut not alcoholic men were broughtindividuallyto the laboratoryon

four occasions separatedby a minimumof 72 hours.All subjectsweretold that they mightreceiveethanolor diazepam challenges.The three sessionsrelevantto the hypothesistestedhere included:(1) oral placeboethanol (approximately 5 ml of ethanoladministered throughthe apparatusdesignedby Mendelsonet al., 1984) and placebo IV saline;(2) low-doseIV diazepam(0.12 mg/kg) taken without dilution from the manufacturer'svial plus placeboethanol;and(3) high-dose diazepam(0.20 mg/kg) plus oral placebo.In this double-blindparadigm,drug consumption wasspreadoutover7 minutes.A fourthsessionusing0.75 ml/kgor oral 95% ethanoldrunkas a 20% by volumesolutionin a carbonatedbeveragealongwith IV salineplacebowasrandomlyinsertedinto the protocol as an internal standardfor comparisonwith our prior alcohol challengeresults. Subjectsarrived at the laboratoryat 7:00 AM after an overnightfast, were givena light breakfastand had two heparin locks insertedin two noncontiguous antecubital

drug infusionand the other for repeatedblood sampling. Dependingon the specifictest, at baseline,approximately 7 to 13 minutes, 30 minutesand about every half hour thereafterover a 3-hour period subjectswere repeatedly evaluatedand bloodwas drawn for drug level determinations as well as for other analysesreportedin other studies (Monteiro et al., in press;Schuckitet al., in press). Levels of diazepamand desmethyldiazepam were determined by the electron-capture gas-liquidchromatography technique(Greenblattet al., 1983). Subjectivefeelingsof intoxicationwere evaluatedon a modifiedSubjectiveHigh Assessment Scale(S•4AS). Thus, at eachtime point subjectswere askedto rate themselves on each of 13 items, with all measuresutilizing a scale rangingfrom 0 (no drug effect) to 36 (maximaldrug effect). The men were instructedto scorethemselvesas 0 at baseline. In addition to the 13 scores, a total SILASscore

incorporatingall itemswas computedfor eachtime point. Using similar repeatedmeasuresover time schedulesas describedabove for the SILAS,levels of body sway or staticataxiawere evaluatedas the meanof threeseparate 1-minuterecordingsof sway separatedby 30 secondsof rest. The scorewas recordedas the averagetotal of the anterior/posteriorplus lateral sway units for the three trials per time point. The body swayapparatuswas modified from that originallyutilized by Moskowitzet al. (1974) in which subjectswere asked to stand as still as possible with their eyes open, feet togetherand hands at their sides.The swayunitswere measuredby a Velcroharness securedaroundthe body at the level of the axilla. The harnesshad ropesattachedperpendicularto the front of the chestand the left side of the body with eachweighted rope passingover a pulley. Changesin body movement causedsubsequent rotation of the pulley which was recordedasmagnetsattachedat 5-centimeterintervalspassed a magneticrecorder(Schuckit, 1985). Data for eachof the SILAS itemsandfor bodyswaywere analyzedusingmethodssimilarto thosereportedin prior publications (Schuckit,1987). Becausebody swayresults at baselineare represented by unitshigherthan0, the first stepin analysesrelevantto that measurewas to determine if therewere any differencesbetweenthe two family history groupsand any differencesin baselinescoresacross the three test sessions by usinga 2 (family history) x 3 (dose at which baselinemeasureswere taken--placebo, low-andhigh-dose diazepam)analysis of variance(ANOVA) focusingon repeatedmeasures andfamily history.A second step,one relevantto all measures,was to determineif there were any time or family historyeffectsduring the placebosessionusinga 2 (family history) x 6 (for body sway) or 9 (for SILAS)time pointsANOVA.Third, for all SHAS items as well as for body sway we carried out a seriesof separate2 (family history) x 3 (dose:placebo, low, high) x 6 (for body sway) or 9 (for SILAS)post-

SCHUCKIT TABLE 1. Demographiccharacteristicsand drinking patternsfor 62 FHP/FHN pairs Student's FHP

Age Height (in.) Weight (lbs) Yearsschooling Age first drink Days/monthdrink Drinks/occasion Drinks/month

FHN

t test (122 df)

(mean + SD)

(mean + SD)

t

p

21.68 + 1.62 71.37 + 2.31 164.5 -+ 21.6 15.4 -+ 1.1 14.1 + 2.7 8.60 + 5.7

22.00 + 1.93 71.29 + 2.34 166.0 + 21.9 15.5 + 1.3 14.2 + 2.5 8.39 -+ 4.39

1.01 0.20 0.39 0.46 0.16 0.23

.31 .84 .69 .64 .87 .81

3.48 -+ 1.66 30.8 + 23.0

3.24 -+ 1.49 28.5 + 19.4

0.85 0.62

.39 .53

ET AL.

603

df, p = .40), with desmethyldiazepam levels of 7.29 ___ 3.80 and 8.40 --- 3.78 ng/ml, respectively(t = -1.38, 78 df, p = .17). Followingthe high-dosechallenge,diazepam levels for the two family history groups were

370.0 ___ 69.13 and 365.0 ___ 55.21 ng/ml, respectively (t = 0.36, 78 df, p = .72), whereasdesmethyldiazepam values for

FHPs

and FHNs

were

15.6--+ 5.38

and

16.7---3.98 ng/ml, respectively(t=-1.11, 78 df, p = .27). The resultsof 2 (family history)x 6 (time points)ANOVAS comparingthe family groupson blood levelsfor diazepamanddesmethyldiazepam bloodlevels at eachdoserevealedno significantfamilyhistorymain nor interactive effects.

baselinedata collectiontime pointsANOVAS. For any itemsdemonstrating a significantdoseor familyhistory effect overall, the fourth step was to determinewhether the low-doseand high-dosediazepamchallengesdiffered significantlyafter controllingfor placeboresults.As has been describedpreviously,the 2 x 3 x 6 or 9 ANOVAS, althoughappropriate,requirethat all family historyor dosedifferencesbe evaluatedby numerousposthoc analysesaccompanied by heavystatisticalpenaltiesthat result in lossof power.As an alternative,we alsocarriedout a 2 (family history) x 2 (dose:low, high) x 6 or 9 (time points)ANCOVAusingplacebotime pointsas a covariate for any items where relevantsignificanteffectswere observed. Results

The demographic and drinkinghistoriesof the 62 FHP and 62 FHN men are presentedin Table 1. Consistent with the prior publicationsusingsubgroups of theseindividualsas notedabove,the subjectsin the two familyhistory groupshad an averageage between21 and 22 years, were closelymatchedon heightand weight,and had approximately15 yearsof schoolingat the time of testing.

Subjective feelingsof intoxication

Table 2 and Figure 1 presentthe resultsof the SHAS self-ratingsat baseline,7 minutes,30 minutesand each

subsequent half-hourduringthe210 minutesfollowingthe consumption of placebo,0.12 and 0.20 mg/kg of diazepam. An overview of the resultsfor each of the 13 mea-

suresandthe subsequent total SILAS scoreis represented in Table2 as the meanfor FHPsandFHNs averagedoverall post-baseline datapoints.Duringthe placebosession,subjectivefeelingscorevalueswereverylow for bothfamily historygroupson all 13 items.The seriesof 2 (family history)x 9 (time points)ANOVAS for placeborevealed significant time effectsfor all measures butno familyhistory main effects.Threeitems(drunk/intoxicated, alcohol/ drug effect, and muddled/confused) revealed Family Historyx Time interactions(F = 2.45, 8/976 df, p < .02 for the most robust difference), reflecting "crossovers"betweenvaluesfor FHPs andFHNs duringthe placebosession,asexemplifiedin the left portionof Figure1. Usingthe actualvaluesat eachtime point,the seriesof 2 x 3 x 9 ANOVAS for each item outlined in Table 3 dem-

These men consumed their first drink on their own at an

onstratedsignificantdoseand time main effectsfor all 13

age of about 14 years, and in the three monthsprior to testingimbibedalcoholon an averageof 8 to 9 daysper month, taking an averageof approximatelythree drinks

Dose x Time interactionsfor all measures.However, no

per occasion.A drink was defined as the amountof etha-

nol containedin 12 oz of beer,4 oz of wine or a single shot (1.5 oz) of 80-proofbeverage.While no man in either grouphad beenprescribeda benzodiazepine in the 6 monthsbeforetesting, 14% of the FHPs and 16% of the FHNs had had suchdrugsprescribedat an earlier date. There were no significant differences between the two family historygroupson any of thesevariables. Due to a proceduralproblem,the diazepamanddesmethyldiazepamblood levels were availablefor only 40 of the 62 pairs.Followingthe lower dosechallenge,the average(--- SD) diazepambloodlevelsduringthetestsession were 220.9 --- 59.94 and 231.44 ___ 50.42 nanograms/ml (ng/ml) for FHPs and FHNs, respectively(t = -.85, 78

subjectivefeelingsand for the total score,and significant

SILAS item demonstrated a significantfamily historymain effect,a FamilyHistoryx Dose,nor anyFamilyHistory x Dose x Time interactions. Only one feeling, "uncomfortable," demonstrated a significantFamily History x Time interaction(F = 2.10, 2/132 df, p = .033). The subsequent seriesof 2 x 2 x 9 ANCOVAS showedsignificant dose and time effects and Dose x Time interactions

for all items demonstratingthe differencesbetweenthe two active doses. There were no differences between fam-

ily historygroupsfor theseAN½OVAS. A more detailedpresentationof the changesin scores

over time during the three test sessions is presentedin Figure 1. The specificitem chosenfor this examplewas one that represents more global feelingsof alcohol/drug effect.The figuredemonstrates a smallchangein the sub-

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Means( -+ SD) over time across210 minutesfor 62 FHP/FHN pairsfor 13 SHAS items Placebo

Low BZ

FHP

FHN

Uncomfortable

.56 + 1.09

.32 --- .67

High Clumsy

.70 + 1.28 .55 + 1.17

.75 --- 1.36 .44 + .78

Muddled

/ NOVEMBER

.48 + 1.02

.39 --- .76

Slurredspeech Dizzy

or confused

.37 + 1.07 .62 + 1.64

.24 --- .56 .49 --- .93

Nauseated

.36 -+ .90

Drunk or intoxicated

.65 --- 1.35

.17 --- .45 .67 - 1.18

Sleepy Time distortion

Drug effect Difficulty concentrating Floating Total SILAS score

.62 --- 1.32 1.25 + 1.92

FHP 2.90 5.91 5.48 4.74 3.38 4.58 1.16 5.37 7.25 4.67 6.48 6.40 4.19

.57 - 1.25 I. 14 + 1.98

.73 + 1.34 .81 --- 1.42 .45 --- .92

.72 --- 1.20 .83--- 1.67 .47 + 1.13

8.14 + 14.02

7.10 + 11.93

SHAS items and the total SHAS score. These are reflected

+ 2.76 +-- 3.97 +-- 3.95 +- 3.87 --- 2.97 --- 3.83 + 1.97 --- 4.00 --- 5.55 --- 4.00

2.56 5.50 4.93 4.47 3.15 4.28 .93 4.96 5.91 4.03

--- 4.30 --- 4.57 + 3.75

5.99 + 4.06 5.87 --- 4.30 3.97 + 3.77

62.49 --- 44.27

jective feelingscoreoverthe placeboperiod,with no family historymain effects.Followingthe low-dosediazepam challenge, there was a rapid increase in feelings that peaked in intensity between 7 and 30 minutes postinfusion,after which scoresrapidlydeclined,approaching baseline150 to 180 minutesafter the drug administration. Following high-dosediazepam, more intense levels of feelingsare reported,with peak effectsbetween7 and 30 minutes,a fairly rapid decline, and a return nearingbaseline feelingsby 180 to 210 minutes. In summary,the infusionof two differentdosesof diazepamand placeboin 62 sonsof alcoholicsand 62 controls resultedin significantdose-relatedchangeson all 13 in

High BZ FHN + 2.29 --- 3.61 --- 3.62 + 3.71 --- 3.04 --- 3.69 - 1.56 +-- 3.65 --- 4.52 - 3.56

58.09 --- 42.21

FHP 5.24 9.10 8.65 7.93 5.82 7.48 2.02 8.54 10.10 7.60

FHN

+ 4.39 --- 5.37 --- 5.52 + 5.57 --- 4.71 --- 5.43 + 2.90 --- 5.21 --- 6.63 --- 5.50

9.93 - 5.48 9.95 - 5.72 6.55 + 5.19 98.92 -

60.84

4.24 8.16 7.66 6.91 5.36 6.42 1.69 7.94 9.23 6.60

+ + -----

3.99 4.52 5.01 5.30 4.80 5.00 2.68 4.74 6.54 4.53 9.05 --- 4.92 9.36 + 5.75 6.17 + 5.02

91.97 --- 62.01

heavierdrinkingpairs(62 men), demonstrating that only for the alcoholsessionwas the family historyby time effect significant(F = 3.50, 7/420 df, p < .001). The data on the subjectiverating of "high" and "drunk" items lookedsimilarwith the only significantfamily historyby time interactionbeingobservedfor ethanol(F = 4.06, 7/ 420 df, p < .001), not for diazepam.No otherfamily history main effect nor interactiveitems were significant, indicatingno evidenceof a family group differentialon the responseto diazepamin this subgroup.

Bodyswayafter diazepamand placebo

Changesin the intensityof the body swayat baseline,

Table 2 demonstratingmean scoreson each item over the

13, 37, 67, 131 and 191 minutes after the three infusions

entire 210 minutes for the three conditions, as well as the

for the 62 pairs are presentedgraphicallyin Figure 3. Consistentwith the visual inspection,there were no significantFHP/FHN differences at baselineat the beginning of any of the three sessions.The two-factor(Family History x Dose) ANOVAfor baselinevaluesacrossthe three sessions demonstrated no significantdose, family history or Family History x Dose Effects. During the placebosession,both family groupsdemonstrateda slightdecreasein swayscoresat 13 minutes,but there were few remarkablechangesduring the approximately3 hoursof testing.Consistent with this interpretation are the resultsof the two-factor(Family History x Time) ANOVAfor the placebosessionthat revealedno significantmain effectsnor any significantinteraction. Following low-dosediazepam,sway scoresincreased rapidlyin bothgroupsat 13 minutesfollowedby a gradual return toward baselineby 131 minutes.After the highdosechallenge,peakeffectswere alsonotedat the earliest time point(13 minutes)with a moregradualreturntoward baselineby 191 minutes.The three-factor(FamilyHistory x Dose x Time) ANOVA revealed significant dose (F = 120.71;2/300 df; p < .001) and time (F = 110.30, 2/300 df, p < .001) effects,but no significantfamily his-

total score.Inspectionof the data and the associatedstatistical analysesreveal no evidenceof a diminishedintensity of responsefor FHPs. The one item for which a Family History x Time interactionwas foundacrossthe three doses,feelingsof being "uncomfortable,"revealed a greater responsefor FHPs than FHNs, not a less intense

one.

Relevantdata were also availableon the family group differencesduring the alcoholsessionfor 30 minutesand beyond,timesthat correspond with our prior alcoholdata. There was a trend for FHPs to show lessoverall response for the majorityof items, includingthe overallalcoholeffect (5.83 - 4.87 vs 6.29 -+ 4.44), but none of thesedifferenceswere significantfor the group of 124 men. However, amongthe heavier drinkersthe FHPs did demonstratesignificantlylower intensitiesof responsefor the moreglobalsummaryitems.In this subsample chosenby a median split on the quantity and frequencyof alcohol consumption over the prior 6 months,the men drankon a averageof 11.3 -+ 1.49 days per month, consumingan average of 4.2-+ 1.49 drinks per occasion.Figure 2 showsthe alcohol/drugeffect item over time for the 31

SCHUCKIT TABLE 3.

605

ET AL.

Resultsof three-factor (FamilyHistoryx Dosex Time)repeated measures ANOVAsfor SHASitemsfor 62 FHP/FHNpairs Family History (1/122)

Df

Dose (2/244)

Family

Family

Time (8/976)

History x Dose (2/244)

History x Time (8/976)

(16/1952)

F = 50.83'

NS

F F F F F F F F F F F F F

NS NS NS NS NS NS NS NS NS NS NS NS NS

Family History x Dose

x Time

(16/1952)

Item

Uncomfortable

NS

F = 98.47a

F = 127.09a

NS

F = 2.10b

High Clumsy

NS NS

F F F F F F F F F F F F F

F F F F F F F F F F F F F

NS NS NS NS NS NS NS NS NS NS NS NS NS

NS NS NS NS NS NS NS NS NS NS NS NS NS

Muddled or confused

NS

Slurred speech Dizzy

NS NS

Nauseated Drunk/intox.

NS NS

Sleepy

NS

Time distortion

NS

Drug effect Difficulty concentrating Floating

NS NS NS

Total score

NS

= = = = = = = = = = = = =

235.21 ' 212.50 a 169.85 ' 123.45 ' 150.81 ' 29.73 ' 210.96 a 148.50 ' 163.11 ' 257.80 ' 224.80 ' 127.63 a 211.75 '

= = = = = = = = = = = = =

217.10 ' 248.18 ' 197.33 ' 163.90 ' 183.19 a 41.27 ' 267.05 ' 121.81 ' 158.72 ' 329.36 a 252.48 ' 189.63 • 271.10 '

= = = = = -= = = = = = =

144.27 ' 123.99 ' 97.50 a 81.49 ' 90.85 ' 13.98 ' 125.17 ' 51.98 a 75.33 ' 156.75 ' 117.04 ' 85.84 • 142.48 a

a p < .000.

Op < .05.

tory main effect. Among the interactions,only the Dose x Time effect was significant(F = 61.91, 2/300 df, p < .001). Thus, therewereno significantlevelsof inter-

this finding is also true for body sway. This dampened alcoholresponseappearsto characterizeabout40% of at leastone large groupof sonsof alcoholicfathers(Schuc-

actioninvolvingfamilyhistory.

kit and Gold, 1988).

In order to determine

whether the effects of low-dose

and high-dosediazepamwere significantlydifferent, we turnedto the 2 x 2 x 6 ANCOVA,controllingfor the effectsof placeboat eachdatapoint. This analysisrevealed a significant doseeffect(F = 83.04, 2/300 df, p < .001) and a significantDose x Time interaction(F = 30.28, 2/300 df, p < .001), demonstratingthe dose-dependent natureof the diazepameffecton overallbody sway,but no family historygroupdifferences. Finally,duringthe ethanolsession,while the 62 FHPs tendedto have lower levels of sway than FHNs (17.1 -+ 7.44 vs 18.5-+ 8.33) the differenceswere not significant. There was a similar trend among the 31 heavier drinkingpairs that were describedabove(16.7-+ 7.00 vs 19.5 ___8.80).

In summary,diazepaminfusionsresultedin robustand dose-dependent changesin body sway for men in both family historygroups.However,despitea weaktrendfor FHPs to demonstrate slightlylessintensechangesin sway, there were no significantfamily historydifferences.For this measure,after ethanolFHP men tendedto sway less than FHNs at all post-baseline time points;howeverno family historydifferenceswere statisticallysignificant. Discussion

Sons and daughtersof alcoholicshave been shownto demonstrate a decreased reaction to ethanol (Schuckit,

1987). In our work, this finding is consistentacrosssub-

jective feelings,someelectrophysiological measuresand hormonalchanges;and, as shownin most laboratories,

The mechanisms contributingto this decreasedresponse to ethanol are unclear. The effects of alcohol in the central

nervoussystem(CNS) are relatively ubiquitous(Koob and Bloom, 1988), making it difficult to determinewhich, if any, physiologicalor neurochemical systemsin the brain are responsible for the alcoholchallengeresults.A logical first stepin attemptingto narrowdownthe biologicalpossibilities

is to determine

if the decreased reaction

is true

for other drugs.The specificagentchosenin the present study,diazepam,hasthe advantageof sharingsomeof the subjectivefeelingsof intoxicationand someneurochemical mechanismswith ethanol (Sudzak et al., 1986), while

having someCNS effectsthat are distinct from thoseof beveragealcohol(Hunt, 1983). Thus, determiningwhether FHP men have a decreasedreaction for diazepam has some implicationsregardingwhether key neurochemical mechanisms that are sharedwith ethanolmight contribute to the decreasedreactionto beveragealcohol.If not, neurochemicaleventsseparatefrom thoserelatedto diazepam are logical areas for further evaluationregarding the dampenedalcoholeffectobservedin prior studies. The presentinvestigationincorporates sampleselection procedures and challengeparadigmcharacteristics that are similar to thoseused in prior alcoholchallengestudies. All subjectswere told that they might receive ethanolor diazepam,and duringthe test sessionsreportedhere they alsodrank a placebobeveragecontaining5 ml of ethanol administeredthroughan apparatusdevelopedby Mendelson et al. (1984). Despitethesesimilaritieswith past experiments,resultsfrom the placebosessionthat resemble prior data and the large numberof subjectsinvolved,the

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22

BA

30

60

90

Time After

120

150

180 210

Plocebo (min)

BA

30

60

Time After

90

120 150

180

210

BA

30

60

90

120

150

180 2_10

Low Diozepam (mln) Time After Hlõh Dl(•zep(•m (mln)

FIGURE1. Mean self-ratingson a 0 to 36 point scalefor alcohol/drug effect at baselineand at 7, 30, 60, 90, 120, 150, 180 and 210 minutesafter placebo,after 0.12 mg/kg IV diazepamand after 0.20 mg/kgIV diazepamfor 62 mawhedpairs with positive(solid line) and negative(brokenline) family historiesof alcoholism.The barsrepresentstandarderror (SE) andBA denotesbaseline.

presentstudyofferslittle evidencethat sonsof alcoholics demonstratea dampenedlevel of subjectivefeelingsor lesschangein body swayafter diazepam.This was observeddespitemodestand clinicallyrelevantbloodlevels of both diazepamand desmethyldiazepam. This conclusion was true for all 13 items of the SILAS,total SILASand

for the body sway results.The lack of generalizabilityto diazepamof the dampenedresponseto ethanolcorroboratesadditionaldata gatheredon a subsetof 37 pairs(74 men) from the presentstudyin which FHPs demonstrated no evidenceof a diminishedhormonalresponseto diazepamfor prolactin,cortisoland growthhormone(Schuckit et al., in press). The focusof the presentinvestigationwas on the diazepamand placebosessions. In creatingthe researchparadigm all possibleefforts were made to maximize the chancesthat all subjectswouldparticipatefully, allowing us to gatherall datafrom the totalof 18 hoursinvolvedin the threekey testsessions. However,we alsowantedto be sure that the present62 pairs would demonstratethe expecteddecreased reactionto alcohol.This requiredsome compromises.

In recentyearsthe best discrimination of the family groupshas beenthe higherdosealcoholchallengeusing 1.1 ml/kg of 95% ethanol.Unfortunately,this doserequiresup to two extra test hoursbecausesubjectsmustbe observedin the laboratoryuntil their blood alcoholconcentrationhas fallen below 30 mg/dl. Also, we estimate

that the data from between5% and 10% of the pairs can be lost with this higherdosebecausethe subjectis unable to drink the requiredamount in the allotted time or becauseof nauseawith emesisat the time of peak alcohol

effect. Thereforerecognizingour emphasison the diazepamdataandwishingto avoidanythingthat mightjeopardizethe cooperation of subjects,we decidedto useonly the lowerdosealcoholchallengein the presentstudy. The resultof this compromiseis that while duringthe ethanol sessions the FHPs still showed a trend for a dimin-

ishedresponse,this only reachedstatisticalsignificance amongthe heavierdrinking pairs, as definedin the Resultssection.We lookedseparatelyat these62 men becauseof trendsfrom prior data indicatingthe possibility that it was in theseheavierdrinkingmen that the family groupdifferentialis strongest.As shownin Figure 2, within this subgroup,while the FHPs did showsignificantlylessresponse to ethanol,therewasno evidenceof a similarphenomenon followingeitherbenzodiazepine dose. The resultsof thisexperimenthaveseveralimplications. First, the data supportthe possibilitythat the dampened responseto ethanolfor FHPs might result from mechanisms that are not shared completely with diazepam. While numeroussuchbiologicalchangescouldbe important, it is logical to considera differentialethanolresponsefor FHPs as comparedto FHNs that relatesto the possiblefluidizing impactethanolhas on neuronalmembranes,related changesin responses mediatedby pros-

SCHUCKIT

ET AL.

607

22

2O 18 16 14

12

10 8 6

BA

30

60

90

120

150

180

210

Time Alter ETOH (rain)

BA

30

60

90

120

150

180

210

BA

30

Time A•ter Low Dlazepam (mln)

60

90

120

150

180

210

Time After High Dlazeparn (mln)

FIGURE2. Mean self-ratings on a 0 to 36 pointscalefor alcohol/drug effectat 30, 60, 90, 120, 150, 180and210 minutesafteralcohol,O.12 mg/kgIV diazepamand after 0.20 mg/kg of diazepamfor the 31 higherquantity-frequency matchedFHP/FHN pairs.

raglandinsor effectson the picrotoxin-sensitive component of the benzodiazepine/gamma aminobutyricacid chloride ionophorereceptorcomplex(Georgeand Collins, 1985; Goldstein, 1983; Hunt, 1983). The results make it less

jective feelingsand body sway, and sampleselectionand evaluationprocedures that are almostidenticalto thoseincorporatedin prior ethanolexperiments.Also, subjectsreceived placeboethanol during all test sessions.Despite

likely that any globaldirect acuteeffectsof ethanolon the benzodiazepinereceptorsare involved. These findings mighthelp directfutureresearchin both humansand animals looking for protean markers associatedwith the dampenedreactionto ethanol. The presentresultsalso make it is lesslikely that psychologicalfactorshave a major role in the differencebetweenFHPs and FHNs after imbibingethanol.This study paradigmusedthe samelaboratory,similar testsof sub-

creasedresponseto diazepam.Thesefindings,makingit lesslikely that psychological setor the laboratorysetting contributedsignificantlyto the results,are consistentwith our prior reportsof similaritiesbetweenFHPs and FHNs on the expectationsof the effects of imbibing alcohol (Schuckit,1987). Also supportingthe lack of importance of generalpsychological mechanisms is the evidencefrom prior studiesthat the dampenedethanolresponseis ob-

these similarities, the FHPs did not demonstrate a de-

80

70

•60 o (..)

>,50 c•

>,40 o

_30 o

20 c-

BA

I

i

50

60

T•me

After

I

90

I

I

120

150

Placebo

I

180 210

(min)

/,

BA

::50 60

I

I

90

120

150 180 210

BA

30

60

90

120 150 180

210

T•me After Low Diazepam (min) Time After High Diazepam (m•n)

FIGURE3. Mean total bodyswayunitsat baselineand at 13, 37, 67, 131 and 191minutesafter placebo,after IV diazepam(0.12 mg/kg) and after IV diazepam(0.20 mg/kg)for matchedpairswith positive(solidline) and negative(brokenline) family historiesof alcoholism.The barsrepresentstandard error (SE) and BA denotesbaseline.

608

JOURNAL

OF STUDIES

ON ALCOHOL

served for electrophysiological and hormonalmeasures. These are much less likely to changein responseto preconceivedexpectations of the effect of ethanol. The datapresentedabovemustbe interpretedin light of relevant caveats. As is true for the diazepam results, whenevergroupdifferences are not observed(i.e., a negative study)it is appropriateto questionif other drugs, alternativedoses,other challengeparadigmsor different testprocedures mighthaveyieldeddifferentresults.Also, the paradigmwouldhavehad greaterstrengthif we had incorporateda fifth sessionwith high-doseethanoland if diazepamresponses had been measuredseveralminutes after the infusion.It is alsopossiblethat the resultsmight have beendifferenthad oral diazepambeenused. Despitethesequestions,the resultssupportthe conclusion that our prior data usingsimilartestingprocedures were not just the resultof the laboratorysetting.These dosesof diazepamwere logicalchoicesbecausethe patternsof changesfollowingthe challenges werequitesimilar to those observed with ethanol, and the low-dose

alcoholchallengedid yield the expectedtrendwith significant differencesamongthe heavier drinking 62 men. A determinationof the resultsobservedwith otherdrugsand other doseswill requireadditionalstudies. In summary,the presentstudydocumentsno evidence of a dampened response to diazepamfor sonsof alcoholic fathers.These family group similaritiesare consistently observedacross13 subjectiveintoxicationitems and for body sway. The resultsparallel anotherreport on a subsampleof thepresentsubjects evaluatinghormonalchanges followingplaceboanddiazepaminfusions.Thesedatahave potentiallyimportantimplicationsfor understanding more about the biological mechanismsthat might contributeto the dampenedethanolresponsefor sonsof alcoholics. Acknowledgment

/ NOVEMBER

1991

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