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FILLMORE, MARCZINSKI AND BOWMAN 663
Acute Tolerance to Alcohol Effects on Inhibitory
and Activational Mechanisms of Behavioral Control*
MARK T. FILLMORE, PH.D., CECILE A. MARCZINSKI, PH.D., AND ANGELA M. BOWMAN, B.A.
Department of Psychology, University of Kentucky, Lexington, Kentucky 40506-0044
ABSTRACT. Objective: Acute alcohol tolerance refers to the obser-
vation of reduced impairment at a given blood alcohol concentration
(BAC) on the descending versus ascending limb of the blood alcohol
curve. Psychomotor performance measures used in human studies of al-
cohol tolerance provide reliable assessments of tolerance but do not iden-
tify specific mechanisms involved in the re-establishment of control, and
little is known about how acute tolerance is expressed in terms of
changes in fundamental mechanisms that regulate and control behav-
ior. This study examined the expression of acute alcohol tolerance to
impaired behavioral control in terms of changes in a drinkers ability to
activate and inhibit behavioral responses as BAC ascended and declined
following a dose. Method: Twenty social drinkers performed a cued go/
no-go task that measured behavioral control after receiving a moderate
dose (0.65 g/kg) of alcohol and a placebo. The development of acute
tolerance was measured by testing behavioral control twice: once dur-
ing the ascending phase and again at comparable BACs during the de-
scending phase of the blood alcohol curve. Results: Inhibitory and
activational aspects of behavioral control both were impaired by alco-
hol. Acute tolerance developed to the impaired activation but not to the
impaired inhibition of behavior. Conclusions: The results highlight the
importance of considering behavioral requirements when testing for the
development of acute tolerance under a dose of alcohol. By modeling
behavioral control as the net effect of countervailing activational and
inhibitory influences, the study suggests that fundamental mechanisms
of control might not display uniform tolerance development. (J. Stud.
Alcohol 66: 663-672, 2005)
THE INTENSITY OF A BEHAVIORAL response to a
dose of alcohol often diminishes with repeated admin-
istrations of the drug. The reduced response is referred to
as tolerance. As tolerance develops, higher doses of alco-
hol might be needed to reinstate the initial effect. Thus,
tolerance to alcohol has become recognized as a factor that
may contribute to alcohol abuse and dependence by en-
couraging the use of escalating doses (American Psychiat-
ric Association, 1994). Alcohol tolerance has also been
observed over the time course of a single dose. A single
dose of alcohol produces a time-dependent change in blood
alcohol concentration (BAC) known as the blood alcohol
curve. BAC initially rises rapidly to a peak and then begins
to decline gradually. These two phases of the curve are
referred to as ascending and descending limbs, respectively.
Early last century, Mellanby (1919) compared the intensity
of alcohol impairment at a given BAC during ascending
including humans (e.g., Hurst and Bagley, 1972; Vogel-
Sprott, 1979; Post et al., 1998). The reduced impairment at
a given BAC on the descending versus ascending limb of
the curve is commonly referred to as acute tolerance,
suggesting that the reduction might be due to some adap-
tive process occurring during physiological exposure to the
drug over time.
Although changes in the intensity of the behavior-im-
pairing effects of alcohol often have a pharmacological or
a biochemical basis (Greenshaw et al., 1989; Kalant, 1989;
Kalant et al., 1971), learning factors also play a role (for a
review, see Vogel-Sprott, 1992). Learning is implicated by
evidence that alcohol tolerance is often environmentally de-
pendent, whereby maximum tolerance is observed when
the drug is taken in the presence of predrug cues that reli-
ably signal its administration (Siegel, 1989; Vogel-Sprott
and Fillmore, 1999). Explanations based on classical con-
663
Received: February 7, 2005. Revision: April 15, 2005.
*This research was supported by National Institute on Alcohol Abuse
and Alcoholism grant R01 AA12895.
Correspondence may be sent to Mark T. Fillmore at the above address,
or via email at: fillmore@uky.edu.
versus descending limbs of the blood alcohol curve.
Mellanby observed that alcohol-induced ataxia in dogs was
more intense at a given BAC during the ascending versus
the descending limb of the curve. Since that time, the find-
ing has been replicated in a number of studies that exam-
ined a wide range of behaviors in a variety of participants,
ditioning principles argue that predrug cues eventually be-
gin to elicit conditioned preparatory responses that
counteract the effects of the drug, thereby producing toler-
ance (Siegel, 1989; Poulos and Cappell, 1991). Human stud-
ies of tolerance to alcohol-induced impairment of complex
psychomotor functions have demonstrated preparatory, com-
pensatory responses by surreptitiously substituting a pla-
cebo for alcohol after a series of alcohol exposures (Beirness
and Vogel-Sprott, 1984; Fillmore, 2003; Sdao-Jarvie and
Vogel-Sprott, 1991). Such tests show above-baseline, com-
pensatory improvements in response to placebo and might
reflect the acquisition of adaptive response strategies to resist
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664 JOURNAL OF STUDIES ON ALCOHOL / SEPTEMBER 2005
the disruptive effects of alcohol (Fillmore, 2003; Vogel-
Sprott, 1992).
The measures of psychomotor performance used in hu-
man studies of alcohol tolerance provide reliable assess-
ments of tolerance but do not identify the specific
mechanisms involved in the re-establishment of control. In
particular, little is known about how tolerance might be
expressed in terms of changes in fundamental mechanisms
of behavioral control. Behavioral control has been modeled
as the net effect of countervailing activational and inhibi-
tory influences (Logan, 1994; Logan and Cowan, 1984;
Miller et al., 1991). Cue-dependent go/no-go tasks have
been used to model inhibitory and activational response
tendencies in human laboratory studies (e.g., Fillmore, 2003;
Miller et al., 1991). The model recognizes that speed of
action is critical for effective behavioral control (Logan,
1994). Consequently, inhibitory and activational mechanisms
of control can be anticipatory, wherein individuals prepare
to act in response to preliminary, antecedent signals that
precede the actual imperative stimulus requiring action.
In this model, cues provide preliminary information regard-
ing the type of imperative target stimulus (i.e., go or stop)
likely to follow a cue. The cues have a high probability of
signaling the correct target (e.g., 80% validity). Inhibitory
and activational tendencies show rapid development of cue
dependence as the preliminary information provided by cues
begins to elicit preparatory processes for the inhibition or
activation of behavior (e.g., Duncan, 1981; Miller et al.,
1991; Posner, 1980; Posner et al., 1980). As a result, re-
sponse activation to go targets becomes faster when sig-
naled by a valid, go cue and slower when signaled by an
invalid, no-go cue. Similarly, the likelihood of inhibiting a
response to no-go targets increases when signaled by a valid,
no-go cue and decreases when signaled by an invalid, go cue.
The cued go/no-go task is a sensitive and reliable mea-
sure of alcohol-induced impairment of behavioral control
(Fillmore, 2003). Previous results have shown that alcohol
disrupts inhibitory and activational response tendencies, as
mation about the expression of learned tolerance in terms
of changes in inhibitory or activational influences on
behavior.
The present study used the cue dependent go/no-go model
to test acute tolerance to a dose of alcohol in terms of
changes in the drinkers ability to activate and to inhibit a
behavioral response in contexts where preliminary cues pro-
vided valid or invalid signals regarding the likelihood that
the response should be executed or suppressed. Social drink-
ers performed the cued go/no-go task after receiving a mod-
erate dose (0.65 g/kg) of alcohol and a placebo. The
development of acute tolerance was measured by testing
subjects behavioral control twice: once during the ascend-
ing phase of the blood alcohol curve and again at compa-
rable BACs during the descending phase of the curve. In
accord with previous research (Marczinski and Fillmore,
2003a), it was expected that alcohol would impair the abil-
ity to activate and inhibit responses during the ascending
phase of the blood alcohol curve. Any degree of acute tol-
erance in a given measure would be evident by reduced
impairment on the descending limb of the blood alcohol
curve. We also predicted that acute tolerance would be af-
fected by the type of cue. Given that behavioral tolerance
can involve preparatory behavioral strategies to restore func-
tion, it was expected that acute tolerance would be facili-
tated by valid preliminary cues. When cues are valid,
subjects can prepare in advance for either the activation or
inhibition of behavior before the actual onset of the target.
As such, valid cues provide the means for subjects to ac-
quire acute tolerance in order to maintain behavioral control.
Method
Subjects
Twenty adults (8 women and 12 men) between the ages
of 21 and 25 years (mean [SD] age of 21.5 [1.0] years)
participated in this study. The racial makeup of the sample
evidenced by increased impulsive errors and slowed re-
sponses under the drug (Abroms et al., 2003; Fillmore, 2004;
Marczinski and Fillmore, 2003a,b, 2005). Moreover, the
model demonstrates the importance of the environmental
context by showing that alcohol impairment of inhibitory
and activational mechanisms is most pronounced in invalid
cue conditions that do not allow for any advanced prepara-
tion of these actions.
Tolerance to the behavior-impairing effects of alcohol is
a complex regulatory phenomenon that likely involves mul-
tiple mechanisms that act to restore normal behavioral func-
tioning under the drug. A reductionist account of tolerance
to behavior-impairing effects of alcohol could be provided
by an examination of the phenomenon at a basic mechanis-
tic level (e.g., inhibition and activation). Application of the
cued go/no-go model could provide important, new infor-
was as follows: black (n = 4), white (n = 15) and Asian
American (n = 1). Subjects completed questionnaires that
supplied demographic information, drinking habits and
physical and mental health status. Exclusionary criteria in-
cluded a self-reported psychiatric disorder, substance use
disorder, head trauma or other injury of the central nervous
system. Volunteers with a Short-Michigan Alcoholism
Screening Test (S-MAST; Selzer et al., 1975) score of five
or higher were excluded from the study. Recent use of ben-
zodiazepines, barbiturates and opiates was assessed by
means of urine analysis. Any volunteer who tested positive
for the presence of any of these drugs was excluded from
the study. Women who were pregnant or breast-feeding, as
determined by self-report and urine human chorionic gona-
dotrophin (HCG) levels, were also excluded from the study.
Participants were recruited via notices posted on community
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FILLMORE, MARCZINSKI AND BOWMAN 665
bulletin boards and by local newspaper advertisements. All
subjects provided informed consent before participating. The
University of Kentucky Medical Institutional Review Board
approved the study. Participants received $60 for their
participation.
Apparatus and materials
Cued go/no-go task. Participants performed a cued go/
no-go reaction time (RT) task that was operated using E-
Prime experiment generation software, version 1.1
(Schneider et al., 2002) and was performed on a personal
computer. A trial involved the following sequence of events:
(1) presentation of a fixation point (+) for 800 ms; (2) a
blank white screen for 500 ms; (3) a cue, displayed for one
of five stimulus onset asynchronies (SOAs = 100, 200, 300,
400 and 500 ms); (4) a go or no-go target, which remained
visible until a response occurred or 1,000 ms had elapsed;
and (5) an intertrial interval of 700 ms.
The cue was a rectangle (7.5 cm 2.5 cm) framed in a
0.8-mm black outline that was presented in the center of
the computer monitor against a white background. The cue
was presented in either a horizontal (2.5 cm 7.5 cm) or
vertical (7.5 cm 2.5 cm) orientation. The go and no-go
targets were the colors green and blue, respectively. They
were displayed on the monitor as a solid hue that filled the
interior of the rectangle cue. Participants were instructed to
press the forward slash (/) key on the keyboard as soon as
a go (green) target appeared and to suppress the response
when a no-go (blue) target was presented. Key presses were
made with the index finger of the preferred hand. The go
and no-go targets were presented in hues that were easily
distinguishable by all participants.
The orientation of the cue (horizontal or vertical) sig-
naled the probability that a go or no-go target would be
tation of cue-target combinations and SOAs was random.
For each trial, the computer recorded whether a response
occurred and, if so, the RT in milliseconds was measured
from the onset of the target until the key was pressed. To
encourage quick and accurate responding, feedback was pre-
sented to the participant during the intertrial interval by
displaying the words correct or incorrect along with the RT
in milliseconds. A test required 15 minutes to complete.
Personal Drinking Habits Questionnaire (Vogel-Sprott,
1992). This questionnaire yielded three measures of a
drinkers current, typical drinking habits: (1) frequency (the
number of drinking occasions per week), (2) customary dose
(ml of absolute alcohol per kg body weight typically con-
sumed during a single drinking occasion) and (3) duration
(time span in hours of a typical drinking occasion).
Biphasic Alcohol Effects Scale (BAES; Martin et al.,
1993). The study also examined subjective stimulant and
sedative effects in response to alcohol. The BAES is a 14-
adjective rating scale of subjective levels of stimulation and
sedation. Seven adjectives described stimulating effects (e.g.,
stimulated, elated), and the remaining seven adjectives de-
scribed sedating effects (e.g., sedated, sluggish). Partici-
pants rated the degree to which the dose produced each
TABLE 1. Cue-target combination probabilities (total trial N = 250)a
Cue
Vertical Horizontal
Trial Trial
Target Trial n proportion Trial n proportion
Go 100 0.8 25 0.2
No-go 25 0.2 100 0.8
aVertical cue predicts go target and horizontal cue predicts no-go target.
displayed. Cues that were presented vertically preceded the
go target on 80% of the trials and preceded the no-go tar-
get on 20% of the trials. Cues that were presented horizon-
tally preceded the no-go target on 80% of the trials and
preceded the go target on 20% of the trials (see Table 1).
Therefore, on the basis of cue-target pairings, vertical and
horizontal cues operated as go and no-go cues, respectively.
The different SOAs (100, 200, 300, 400 and 500 ms) be-
tween cues and targets encouraged participants to pay at-
tention to the cues, and the variability and randomness of
the SOAs prevented the participants from anticipating the
exact onset of the targets.
A test consisted of 250 trials that presented the four
possible cue-target combinations (see Table 1). An equal
number of vertical (125) and horizontal (125) cues were
presented before an equal number of go (125) and no-go
(125) target stimuli. Each cue-target combination was pre-
sented at each of the five SOAs, and an equal number of
SOAs separated each cue-target combination. The presen-
feeling on an 11-point Likert-type scale ranging from 0
(not at all) to 10 (extremely). The stimulation and se-
dation item scores were summed separately to provide a
total subscale score for stimulation and sedation (score
range: 0-70).
Subjective intoxication. Participants also reported their
level of subjective intoxication, expressed by their estimate
of how many standard drinks would be required to achieve
their current level of intoxication. Subjects providing their
rating in terms of either bottles of beer (5% alcohol) or
fluid ounces of liquor (40% alcohol), whichever beverage
was most familiar to the subject. Both scales ranged from 0
to 10, in 0.5 increments. The scale has been used in previ-
ous research and shows dose-dependent effects of alcohol
on subjective intoxication (e.g., Marczinski and Fillmore,
2003b).
BACs. BACs were determined from breath samples mea-
sured by an Intoxilyzer, Model 400 (CMI, Inc., Owensboro,
KY).
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666 JOURNAL OF STUDIES ON ALCOHOL / SEPTEMBER 2005
Procedure
Individuals who responded to the advertisements called
the laboratory and participated in a phone intake screening
interview. Volunteers were told that the purpose of the ex-
periment was to study the effects of alcohol on performance.
Interested volunteers then made appointments to partici-
pate in three laboratory sessions: a familiarization session
and two test sessions. All sessions were conducted in the
Human Behavioral Pharmacology Laboratory of the De-
partment of Psychology and began between 12:00 PM and
6:00 PM. The sessions occurred no less than 24 hours apart
and no more than 7 days apart. Prior to sessions, partici-
pants provided urine samples, which were tested for the
presence of drug metabolites (On Trak TesTstiks, Roche
Diagnostics Corporation, Indianapolis, IN) and HCG (Main-
line Confirms HGL, Mainline Technology, Ann Arbor, MI).
Breath samples were also provided at the beginning of each
session to verify a BAC of 0 mg/dl.
Familiarization. During familiarization, subjects provided
informed consent, were weighed and completed question-
naires. A color vision test required subjects to distinguish
between the green and blue colors used as go and no-go
targets in the task in order to ensure the ability to discrimi-
nate between the stimuli. The task requirements were then
explained to the subjects. Subjects were instructed to press
the forward slash key (/) on the keyboard as quickly as
possible whenever a go (i.e., green) target appeared and to
inhibit this response whenever a no-go (i.e., blue) target
appeared. They were encouraged to respond in the fewest
milliseconds and were told that the computer would dis-
consisted of four parts carbonated mix with 3 ml of alcohol
floating on the surface. The glasses were sprayed with an
alcohol mist that resembled condensation and provided a strong
alcoholic scent as the beverages were consumed. Previous
research has shown that individuals report that this bever-
age contains alcohol (e.g., Fillmore and Blackburn, 2002).
At each session, subjects were tested twice on the cued
go/no-go task: at 30 minutes and again at 90 minutes after
drinking began. Based on prior studies of the active alco-
hol dose (e.g., Fillmore and Weafer, 2004; Marczinski and
Fillmore, 2003a,b), subjects were expected to achieve an
average BAC of 65 mg/dl at 30 minutes that would con-
tinue to rise to an approximate peak of 80 mg/dl at 60
minutes and descend back to 65 mg/dl by 90 minutes. BAC
was measured at eight intervals throughout the session, in-
cluding immediately prior to and immediately following
each test. The intervals were as follows: 20, 30, 45, 60, 75,
90, 105 and 140 minutes after drinking began. Breath
samples were also obtained at these times during the pla-
cebo session, ostensibly to measure subjects BACs. After
each test, subjects completed the BAES and subjective in-
toxication scale. Once the session was complete, subjects
remained at leisure in a waiting room until their BAC fell
below 20 mg/dl. They were given a meal and read maga-
zines or watched movies. On completing the final session,
participants were paid and debriefed.
Criterion measures and data analyses
The two primary measures were subjects speed of re-
sponding to go targets (response activation) and their fail-
play the reaction time in milliseconds following each re-
sponse. Subjects then performed a test to familiarize them
with the task. A single test is sufficient to produce cue-
dependent responding (Marczinski and Fillmore, 2003b).
Test sessions. Performance was tested under two dose
conditions: a moderate alcohol dose (0.65 g/kg) and a pla-
cebo dose (0.0 g/kg). Doses were administered on separate
sessions, and dose order was counterbalanced across sub-
jects. The 0.65-g/kg alcohol dose produces an average peak
BAC of 80 mg/dl and was chosen based on prior research
that showed the dose reliably impairs the ability to quickly
activate and inhibit responses as measured by the cued go/
no-go task (Fillmore and Weafer, 2004; Marczinski and
Fillmore, 2003a,b). The research assistant who administered
the cued go/no-go task was blind to the dose condition.
Doses were calculated based on body weight and were
administered as absolute alcohol divided equally into two
drinks, each containing one part alcohol and three parts
carbonated mix. Subjects had 1 minute to finish each drink,
and the drinks were served 4 minutes apart. This dosing
procedure produces the peak BAC at approximately 60 min-
utes from the onset of drinking (Fillmore and Blackburn,
2002). The placebo was served in the same manner and
ures to inhibit responses to no-go targets (failures of
response inhibition).
Response activation. Response activation was measured
by the RT to go targets. Longer RTs indicate impaired re-
sponse activation. A mean RT score for a subject was cal-
culated for each cue. Responses with RTs less than 100 ms
and greater than 1,000 ms were excluded. These outliers
were infrequent, occurring on average in less than 1.5% of
the trials for which a response was observed. RT scores on
the ascending limb of the blood alcohol curve were com-
pared with RT scores on the descending limb. This was
tested by a 2 Dose (0.0 g/kg, 0.65 g/kg) 2 Limb (test 1 vs
test 2) 2 Cue (go cue vs no-go cue) within-subjects analy-
sis of variance (ANOVA).
Failure of response inhibition. Failure of response inhi-
bition was measured as the proportion of no-go targets in
which a subject failed to inhibit a response. These p-inhibi-
tion failure scores were calculated for each cue condition
(go and no-go) on each test. The p-inhibition failure scores
were analyzed by a 2 (Dose) 2 (Limb) 2 (Cue) within-
subjects ANOVA.
Omission errors were also recorded. These errors occurred
when subjects failed to respond to go targets. Omission
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FILLMORE, MARCZINSKI AND BOWMAN 667
errors were infrequent and occurred on less than 2% of go
target trials (~2 trials per test).
Specific hypotheses regarding alcohol impairment and
acute tolerance were assessed by simple effect, planned com-
parisons using dependent t tests comparing dose conditions,
tests and subjective effects. Although no gender differences
were predicted, all analyses were first conducted with gen-
der as a factor. No gender differences were observed for
the dependent measures of response activation and failures
of response inhibition (p > .27). Initial analyses also in-
cluded dose order as a factor. No effects involving dose
order were obtained for any measure (p > .35).
Results
Drinking habits
The sample reported a mean drinking frequency of 2.2
(1.4) times per week, with a mean dose per occasion of 1.0
(0.6) ml/kg. For a person weighing 70 kg, this alcohol dose
would approximate 4.4 bottles of beer containing 5% alco-
hol per volume. The mean duration of drinking was 3.3
(1.1) hours.
Blood alcohol concentrations
Figure 1 plots subjects mean BACs under alcohol at
each interval when breath samples were obtained. The fig-
ure shows that BACs ascended to a peak of 82.9 (11.2)
mg/dl at 60 minutes after drinking began. At 140 minutes
after drinking BAC declined to 57.5 (11.2) mg/dl. For test
1, the mean BAC at the start of the test (30 minutes) and at
its completion (45 minutes) was 67.6 (13.1) mg/dl and 75.2
(10.8) mg/dl, respectively. For each subject, these two start-
finish BACs were averaged to yield a test-specific average
BAC that represented the average BAC of the subject dur-
ing the 15-minute interval in which test 1 was performed.
For the entire sample, the average, test-specific BAC for
test 1 was 71.4 (11.2) mg/dl.
For test 2, the mean BAC at the start of the test
(90 minutes) and at its completion (105 minutes) was 73.5
(9.7) mg/dl and 67.9 (10.5) mg/dl, respectively. These two
FIGURE 1. Mean blood alcohol concentrations (BACs) under alcohol at each interval when breath samples were obtained. Capped vertical lines show
standard error of the mean.
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668 JOURNAL OF STUDIES ON ALCOHOL / SEPTEMBER 2005
start-finish values were also averaged to yield a test-spe-
cific average BAC for test 2. For the entire sample, the
average, test-specific BAC for test 2 was 70.7 (10.2) mg/
dl. Thus, the test-specific average BACs at each limb of
the blood alcohol curve were nearly identical, and a pair-
samples t test found no significant difference between the
two measures (p = .75). No detectable BACs were observed
in the placebo condition.
Task performance
Response activation. A 2 (Dose) 2 (Limb) 2 (Cue)
ANOVA of RT to go targets revealed a significant main
effect of cue (F = 30.2, 1/19 df, p < .01) and significant
interactions between dose and limb (F = 4.9, 1/19 df, p =
.04) and between limb and cue (F = 12.8, 1/19 df, p < .01).
Figure 2 shows the mean RT to go targets, as a function of
dose, test and cue. The figure illustrates the cue depen-
dency of RT, with faster RT following go (valid) cues and
shows that alcohol generally slowed RT compared with pla-
cebo. The figure also shows acute tolerance in the go cue
condition. Here, alcohol initially slowed RT compared with
placebo during the ascending limb of the blood alcohol
curve. However, during the descending limb the slowing
effect of alcohol was absent and the mean RTs under alco-
hol and placebo were nearly identical. The acute recovery
of response activation under alcohol in the go cue condi-
tion was confirmed by a simple effect comparison that
showed significantly faster RT during the descending limb,
as compared with the ascending limb of the blood alcohol
curve (t = 5.0, 19 df, p < .01). By contrast, no significant
difference in RT was observed over the same two testing
periods under placebo (p = .240).
No acute tolerance to alcohol-induced slowing of RT
was evident in the no-go cue condition. Simple effect
comparisons of RT found no significant differences between
FIGURE 2. Mean reaction times (RTs) to go targets, as a function of dose, test and cue. Capped vertical lines show standard error of the mean.
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FILLMORE, MARCZINSKI AND BOWMAN 669
testing periods under alcohol or following placebo
(p > .140).
Failure of response inhibition. A 2 (Dose) 2 (Limb)
2 (Cue) ANOVA of p-inhibition failures to no-go targets
revealed significant main effects of cue (F = 21.3, 1/19 df,
p < .01) and dose (F = 5.8, 1/19 df, p < .03) and a signifi-
cant interaction between limb and cue (F = 4.8, 1/19 df, p
= .04). No significant interaction involving dose and limb
was obtained (p > .36). Figure 3 illustrates the cue depen-
dency of response inhibition, with less p-inhibition failures
following the no-go (valid) cues. The figure also shows
that alcohol generally increased p-inhibition failures. The
figure shows no evidence of reduction (i.e., tolerance) in p-
inhibition failures under alcohol over the two testing peri-
ods in either cue condition. Simple effect comparisons of
p-inhibition failure scores found no significant differences
between the two tests under alcohol or following placebo,
in either go or no-go cue conditions (p > .12).
Subjective effects
Mean subjective ratings for the dose conditions are pre-
sented in Table 2. Dose and limb effects on each subjective
effect were analyzed by separate 2 (Dose) 2 (Limb) re-
peated measures ANOVAs.
Stimulation. Stimulation ratings showed a significant Dose
Limb interaction (F = 7.9, 1/19 df, p = .01). Table 2
shows greater stimulation under alcohol compared with pla-
cebo. Moreover, the table shows that, under alcohol, the level
of stimulation decreased from the ascending to the descend-
ing limb. This difference was confirmed by a simple effect
comparison between ascending and descending limbs un-
der alcohol (t = 4.0, 18 df, p < .01). The slight decrease in
stimulation ratings over the two tests in the placebo condi-
tion was also statistically significant (t = 2.8, 18 df, p = .01).
Sedation. Sedation ratings showed a main effect of dose
(F = 8.5, 1/19 df, p < .01). Table 2 shows greater sedation
FIGURE 3. Mean proportion of failures to inhibit responses to no-go targets, as a function of dose, test and cue. Capped vertical lines show standard error
of the mean.
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670 JOURNAL OF STUDIES ON ALCOHOL / SEPTEMBER 2005
under alcohol compared with placebo. No significant Dose
Limb interaction was obtained (p = .11), and Table 2
shows that the level of sedation was fairly consistent across
tests under alcohol and under placebo.
tests under the dose, regardless of task cue conditions. The
study also found some evidence for acute tolerance to the
subjective effects of alcohol. The BAES showed acute tol-
erance to subjective stimulation but not to subjective seda-
tion under the dose. Studies of the BAES typically find
that alcohol exerts a biphasic effect on subjective states of
arousal in which greater stimulant effects are reported dur-
ing the ascending limb of the blood alcohol curve and in-
creased sedation is reported during the descending limb of
the curve (Martin et al., 1993).
Evidence for acute alcohol tolerance to impaired activa-
tionbut not impaired inhibitionof behavior is a poten-
tially important finding that cannot be attributed to
differences in task stimuli or subject characteristics in the
present study. The evidence was obtained from a within-
subjects design, using a single task that provided concur-
rent assessment of activational and inhibitory aspects of
behavioral control. The scheduling of tests was based on
TABLE 2. Mean subjective effect ratings under two dose conditions
Alcohol Placebo
Test 1 Test 2 Test 1 Test 2
Measure Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Stimulation
(BAES) 32.8 (22.4) 19.9 (18.1) 9.9 (12.9) 7.0 (11.3)
Sedation
(BAES) 19.0 (16.2) 22.7 (18.3) 9.7 (15.7) 6.1 (9.0)
Intoxication (no.
of standard drinks) 4.1 (1.7) 3.1 (2.0) 1.0 (1.1) 0.5 (0.7)
Notes: BAES = Biphasic Alcohol Effects Scale; scores ranged from 0 to
70.
Subjective intoxication. Intoxication ratings showed sig-
nificant main effects of dose (F = 66.7, 1/19 df, p < .01)
and limb (F = 10.1, 1/19 df, p < .01). No significant Dose
Limb interaction was obtained (p = .091). Table 2 shows
greater intoxication under alcohol compared with placebo
and a general decrease in intoxication ratings across tests
in both dose conditions. In addition, all of the subjects re-
ported that the placebo beverage contained at least some
alcohol, indicating that the placebo appeared credible.
Discussion
This study examined the expression of acute tolerance
to alcohol-induced impairment of behavioral control in terms
of changes in a drinkers ability to activate and to inhibit a
behavioral response as BAC ascended and began to decline
under the dose. The study showed that inhibitory and
activational aspects of behavioral control were both im-
paired by alcohol. Compared with placebo, alcohol slowed
response activation and increased failures to inhibit re-
sponses. As in previous studies (e.g., Fillmore and Weafer,
2004; Marczinski and Fillmore, 2003b), impairment was
most pronounced in the invalid cue conditions. The study
also demonstrated acute tolerance to the impairing effect of
alcohol on response activation. Alcohol slowed RT com-
pared with placebo during the ascending limb of the blood
alcohol curve. During the descending limb, the slowing ef-
fect of alcohol was absent and the mean RTs under alcohol
and placebo were nearly identical. This acute tolerance ef-
fect was specific to the valid cue condition, whereby a valid,
preliminary go cue was presented before the actual go tar-
get that required response activation. With regard to re-
sponse inhibition, no acute tolerance to alcohol-induced
impairment was observed under the active dose. Compared
with placebo, alcohol increased failures to inhibit responses
to no-go targets, and this impairment did not diminish over
considerable prior research on the pharmacokinetic profile
of the active dose. The average BACs during the 15-minute
testing periods on each limb of the blood alcohol curve
were nearly identical, and thus the reduced impairment ob-
served on the descending limb cannot be attributed to limb
differences in BAC. Differences in the recovery of impaired
activation and inhibition during the dose also cannot be
attributed to any speed-versus-accuracy trade-off. In a speed-
accuracy trade-off, any alcohol-induced slowing of RT
should actually improve response inhibition by allowing
more time to inhibit responses when necessary. Instead, the
alcohol-induced slowing of response activation in the present
study was accompanied by a reduction in the ability to
inhibit responses.
Moreover, evidence of acute recovery of response acti-
vation but not response inhibition is consistent with basic
theories of behavioral control, which assume some degree
of independence between these control mechanisms (Lo-
gan, 1994; Logan and Cowan, 1984) and previous research
that shows drugs can exert dissociative effects of these two
mechanisms (Fillmore et al., 2003; Marczinski and Fillmore,
2003a). The present study was based on a model that rec-
ognized the anticipatory nature of the two mechanisms. We
predicted that any acute tolerance to alcohol impairment of
behavioral control mechanisms should be facilitated by the
presence of valid preliminary cues that allow advanced
preparation of an appropriate response. In accord with this
hypothesis, the acute alcohol tolerance to impaired response
activation was specific to the valid cue condition where
preliminary go cues allowed subjects time to prepare a re-
sponse before presentation of the actual go target. The im-
portance of response preparation to tolerance development
in the present research fits well with various learning-based
accounts of behavioral tolerance that emphasize its antici-
patory nature. It is well known that alcohol tolerance can
be facilitated in situations where drinkers can anticipate
Page 9
FILLMORE, MARCZINSKI AND BOWMAN 671
specific alcohol effects or specific consequences for exhib-
iting those effects. These observations have been explained
in terms of classical conditioning (e.g., Hinson and Siegel,
1980), operant learning (e.g., Wolgin, 1989) and in terms
of a unified learning theory, based on the concept of ex-
pectancy (Vogel-Sprott and Fillmore, 1999). The present
findings provide further support for the anticipatory nature
of tolerance by demonstrating how tolerance development
can be influenced by anticipatory processes involved in pre-
paring the actual response under the drug.
The results also highlight the importance of considering
behavioral requirements when testing for the development
of acute tolerance under a dose of alcohol. By modeling
behavioral control as the net effect of countervailing
specific BAC (OConnor et al., 1998). The clamping tech-
nique appears quite effective in holding BAC stable in an
individual and may be a useful procedure to further inves-
tigate differences in acute tolerance to impaired inhibition
and activation of behavior as a function of exposure time
as BAC is held constant.
The findings might also be relevant to processes under-
lying the development of chronic alcohol tolerance that de-
velops over a long-term course of repeated alcohol
administrations. Some theories suggest that acute tolerance
contributes to the development of chronic tolerance, be-
cause they both share some common underlying adaptive
processes (e.g., Kalant et al., 1971). This hypothesis has
been supported by some laboratory research (Beirness and
activational and inhibitory influences, the study suggests
that fundamental mechanisms of control might not display
uniform tolerance development. Evidence for a possible lag
in tolerance development to inhibitory versus activational
mechanisms suggests that, as blood alcohol declines, drink-
ers response inhibition might continue to be impaired, de-
spite having an unimpaired ability to activate responses (see
also Pihl et al., 2003; Schweizer et al., 2004). Evidence
that acute tolerance results in such an activational bias of
behavior would have important implications for understand-
ing some of the behaviorally disruptive effects of the drug.
An activational bias in a drinking situation could increase
the likelihood of disinhibited behavior under the drug, es-
pecially in the presence of environmental cues that insti-
gate responses that are normally suppressed. Thus, an
activational bias could increase the likelihood of aggres-
sive actions or heavy episodic drinking. Although the find-
ings of the current study were based on simple aspects of
behavioral control (e.g., inhibiting or activating a key press
response), these basic aspects of control are the building
blocks of the higher-order cognitive processes. Many fun-
damental inhibitory and activational influences on cogni-
tive and perceptual processes are considered to operate in a
bottom-up fashion, exerting increasing influence at each
stage of higher-order processing (Barkley, 1997; McClelland
and Rumelhart, 1981).
A variety of methods have been used to study acute
alcohol tolerance in humans. The present findings were
based on comparisons between ascending and descending
limbs of a blood alcohol curve following a single adminis-
tration of alcohol. Although BACs can be matched across
limbs, there are usually differences in the rate of change in
BAC between limbs. The rate of rise in BAC is usually
swifter than the rate of descent. These rate differences could
also affect impairment (e.g., Fillmore and Vogel-Sprott,
1998). Acute alcohol tolerance also has been studied using
frequent administrations of low doses to achieve a steady-
state BAC over time within a session (Kaplan et al., 1985)
and more recently by intravenous ethanol infusion tech-
niques designed to clamp the infusion rate to maintain a
Vogel-Sprott, 1984). To the extent that acute and chronic
tolerance is determined by common adaptive processes, tol-
erance development to impaired inhibitory and activational
mechanisms might also differ over the course of repeated
exposures. The possibility that chronic tolerance might not
develop uniformly to impaired activation and inhibition of
behavior has yet to be examined.
Acknowledgment
The authors acknowledge Brooke Dillon for her assistance in data
collection.
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