Psychopharmacology(1990) 102:207-212

Psychopharmacology
Springer-Verlag 1990

Acute tolerance to ethanol using drug discrimination

and open-field procedures in rats
Arto J. Hiltunen 1' 2 and Torbj0rn U . C . J~irbe 2

1 Universityof Uppsala, Department of Clinical Psychology,Box 1225, S-751 42 Uppsala, Sweden

2 Universityof Uppsala, Department of Psychology,Box 1854, S-751 48 Uppsala, Sweden
Received September 6, 1989 / Final version April 18, 1990

Abstract. This study examined the phenomenon of acute

tolerance to ethanol (ETOH) using drug discrimination
learning (DDL), and open-field (OF) procedures. In
DDL, rats were trained to discriminate between ETOH
(1.2 g/kg) and saline. Doses of ETOH lower (0.6 and 0.9
g/kg), or higher (1.8 and 2.4 g/kg) than the training dose
were tested to examine possible influence of ETOH pretreatment doses on the expression of acute tolerance. To
assess concentrations of ETOH in the organism, a rebreathed air procedure was used. Equal concentrations
after different ETOt-I doses were achieved by postponing
the tests until sufficient time had elapsed. Only doses of
ETOH higher than the training dose produced acute
tolerance in the DDL procedure. For the response-time
data no acute tolerance was observed. In the OF experiment, the occurrence of acute tolerance was examined for
different spontaneous behaviours in drug-naive animals.
At equal ETOH concentrations, the group examined
during the descending phase of intoxication (1.8 g/kg, 60
min post-injection), reared significantly more than the
group tested during the ascending phase (1.5 g/kg, 10 min
post-injection). Other OF behaviours did not differ significantly between the two time intervals. Thus, it is
suggested that acute tolerance is seen both in ETOH
naive and in ETOH pre-exposed rats. However, in DDL
acute tolerance was observed only when doses higher
than the training dose of ETOH were evaluated.

Key words: Acute tolerance

tion Open-field - Rats

ETOH - Drug discrimina-

Acute tolerance to ethanol (ETOH) is commonly defined

as a reduced effect of ETOH during the descending
phase, as compared to the ascending phase of the ETOH
intoxication when comparisons are made at equal ETOH
concentrations in the blood (Mellanby 1919; Moskowitz
et al. 1979). This is also referred to as the Mellanby effect
Qff~orint requests to: A.J. Hiltunen

or the acute recovery effect (Moskowitz et al. 1979; Vogel

Sprott 1979). The early reports of acute tolerance to
ETOH were quite consistent in supporting the existence
for such a phenomenon (e.g. Mellanby 1919; Goldberg
1943; Ekman et al. 1964). However, one factor usually
not taken into consideration is the discrepancy between
ETOH concentrations in venous and arterial blood
during the early phase of ETOH intoxication (Martin et
al. 1984). When measuring ETOH concentrations in venous or capillary blood, the ETOH level in the brain
would be underestimated during the early, ascending
part of intoxication (Jones 1978). The unequal distribution of ETOH in the organism shortly after ETOH intake
(Gostomzyk and Streffer 1969; Gostomzyk et al. 1969;
Sunahara et al. 1978) would have 'facilitated"
demonstrations of acute tolerance (e.g. Ekman et al.
1964; Franks et al. 1974; Tullis et al. 1977; Campanelli
et al. 1988).
Using a moving belt procedure and measuring the
ETOH concentrations directly from cortical brain tissue,
LeBlanc et al. (1975) reported on the occurrence of acute
tolerance in ETOH naive animals. In our laboratory, we
have used rebreathed air as an indicator of brain ETOH
concentrations, because of the good correlation between
concentrations of ETOH in the lungs and arterial blood,
and consequently also in the brain (Gostomzyk and
Streffer 1969; Gostomzyk et al. 1969). We found no
evidence of acute tolerance when investigating the discriminative stimulus properties of ETOH in a drug discrimination learning (DDL) procedure (Hiltunen et al.
1989). The discriminative choice behaviour of the rats
correlated well with the concentrations of ETOH in rebreathed air. Thus, when concentrations of ETOH in
rebreathed air rose there was a concomitant, dose-related
increase of ETOH injection-appropriate choice behaviour; when the concentrations decreased, there was a
corresponding decline of ETOH related responding. The
principal differences between the study of LeBlanc et al.
(1975) and our study (Hiltunen et al. 1989) were the
behaviour studied and the use of naive animals (LeBlanc
et al. 1975), as opposed to our ETOH experienced ani-

208

mals (Hiltunen et al. 1989). Thus, it seemed possible that

in a DDL experiment animals might have become at least
partly tolerant to the training drug, in this particular case
ETOH.
In the present study, E T O H - D D L trained rats were
tested with doses of ETOH both higher and lower than
the training dose; both the choice behaviour and the
response times were considered. Different behaviours
may disclose different susceptibility with regard to acute
tolerance (e.g., Vogel-Sprott 1979). Equal, comparable
concentrations of ETOH were achieved by postponing
the behavioural tests until sufficient time had elapsed
since administration. Additionally, in a second experiment, acute tolerance was studied in drug-naive animals
using an open-field (OF) test. Two different ETOH
groups were used. One group was examined 10 min after,
and the other group 60 min after the ETOH administration. At the time of the OF test, both groups exhibited
equal concentrations of ETOH in breath.
Methods
Animals. Female Sprague-Dawley rats (ALAB AB, Sollentuna,
Sweden) were used for the D D L (N= 20), and for the OF (N = 44)
experiments. The animals were housed individually (DDL), or in
groups of five or six, under standard laboratory conditions (temperature 20-22 C; relative humidity 50-60%; and 12 h light-dark
cycle, lights on 7 a.m.). The DDL rats were deprived of food in
order to maintain their weights at 75-80% of their expected freefeeding levels. Water (DDL), or food (R3 lab chow, Ewos, S6dert/ilje, Sweden) and water (OF), were freely available in the home
cages. The average (:kSEM) free-feeding weights at the time of
the initiation of D D L training or the start of OF testing were 199.5
(0.9) g, and 243.8 (1.8) g, respectively.

Apparatus. The operant chambers have been described elsewhere in

more detail (e.g. Hiltunen and Jfirbe 1986; Jfirbe and Hiltunen
1987). The chambers contained two response levers separated by a
recess in which a liquid food could be presented (powdered R3 lab
chow, Ewos, S6dertfilje, Sweden, containing 1% starch mixed with
tap water, approximately 50%). A retractable drinking cup was
presented for 4 s as a means of delivering the reward. Lever presses
were recorded by an Amstrad microcomputer connected to the
chambers through a LVB interface (Med Associates, East Fairfield,
VT, USA), and the contingencies of reinforcement were scheduled
by the modified version (Spencer and Emmett-Oglesby 1985) of the
program originally described by Emmett-Oglesby et al. (1982).
The OF arena was a wooden box (60 x 60 x 50 cm) with an open
top, and the floor divided into 16 squares (15 x 15 cm). A circle was
marked in the centre of the field. The squared floor was covered with
an acrylic plate (60 x 60 cm). Illumination was provided by the
normal room light (215 Lux at the floor level of the OF box
according to measurements using a Spectra Photometer, model
301).
Drug-discrimination training. Drug discrimination training proceeded as described elsewhere (e.g. Hiltunen and J/irbe 1986; J/irbe
and Hiltunen 1987). The animals had to press the injection-appropriate lever 10 times (FR 10) to get access to the reinforcer. Which
lever was correct depended upon whether ETOH (1.2 g/kg) or the
vehicle (physiological saline, 12 ml/kg) had been administered 10
min prior to the session. This injection - training interval was based
on previous results (Hiltunen et al. 1989). These data suggested a
rapid onset of the ETOH cue in rats, as determined by D D L tests
and a rebreathed air procedure for evaluating ETOH concentrations in the system; the decline of the ETOH concentration curve

was apparent as early as 15 min after ETOH administration. Responses on the inappropriate lever had no programmed consequences. The rats were trained during daily 10-min sessions, 5 days a
week (Monday through Friday). In order to avoid potential interanimal cues, the order in which the animals were trained during
a given day was varied (Extance and Goudie 1981).

Drug-discrimination testin O. After the animals had correctly selected

the injection-appropriate lever at the onset of each training session
for at least eight out of ten consecutive training days, test sessions
were introduced. Correct responding is defined as a rat should not
have pressed the "wrong" lever more than 9 times before switching
to the "correct" lever during the daily first schedule component; this
is usually referred to as the first reinforcement being equal to or less
than 19. The rationale for examining acute tolerance in the drug
discrimination procedure was to compare ETOH appropriate responding at equal concentrations of ETOH in rebreathed air. Equal
concentrations of ETOH were achieved by postponing testing until
sufficient time had elapsed since the administration of ETOH. The
time interval of 10 min corresponds to the ascending limb, and the
longer time intervals represent the descending limb of the ETOH
intoxication curve (Hiltunen et al. 1989 ; unpublished observations).
Unlike the regular training or maintenance sessions, both levers
were operative throughout the test sessions, and the animals consequently could gain reinforcement by working on either or both of
the two levers. The reward was delivered according to the schedule
requirements of the training sessions (FR-10). Each test session
ended after the animals had received six rewards, or 10 rain had
elapsed since the initiation of the test sessions. Test sessions were
mostly conducted only once a week (Fridays). Test drugs and doses
were studied in a mixed order. No test sessions were run unless
responding during the two preceding training sessions had been
correct.

A reduction of ETOH appropriate responding at equal concentrations of ETOH would indicate the occurrence of acute
tolerance. Concentrations of ETOH in rebreathed air of rats were
measured using a method modified after Pohorecky and Brick
(1982), as recently described by us (Hiltunen et al. 1989). We found
a very good correlation (+ 0.95) between concentrations of ETOH
in arterial blood and in rebreathed air. As noted in the Introduction,
concentrations of ETOH in rebreathed air provide a good indirect
measure of the levels in brain. Additionally, a positive correlation
(+ 0.65) occurred between the ETOH discriminative response and
concentrations of ETOH in rebreathed air (Hiltunen et al. 1989).
Hence, the time course were similar for the two measures.

OpenJ~eld procedure. On the day of examination, the rats were

placed in individual macrolone cages. Two groups of the animals
were tested 10 min (1.5 g/kg and 15 ml/kg), and the other two
groups (1.8 g/kg and 18 ml/kg) 60 rain after injections of ETOH and
saline, respectively. Choice of dose/time combinations to obtain
equivalent concentrations for the ascending and descending limbs
of the ETOH intoxication curve were based on the data presented
by Hiltunen et al. (1989), as well as unpublished observations. At
the time of testing, the rat was placed in the centre of the OF arena
and allowed to explore the field for 5 rain. Records were kept of the
behaviours described and defined by Hiltunen et al. (1988), and
Jfirbe and Hiltunen (1987). The acrylic plate was rinsed with water
between trials to minimize odours from the previously tested animal.
Drugs. Ethanol (99.5%), diluted with saline to achieve a 10% concentration (w/v), was administered IP at doses ranging between 0.6
and 2.4 g/kg, Doses were achieved by varying the volumes administered, thus keeping the concentration of the ETOH solution constant (Linakis and Cunningham 1979).
Data analysis. The results from the DDL experiment are presented
as i) average percentage of responses on the drug-associated lever
out of the total number of responses emitted during a test session;

209
lO0.

response-time, i.e. the time in seconds to complete the first

reinforcement ratio, and the mean time (in seconds) to complete the
remaining five reinforcement ratios. Concentrations of ETOH in
rebreathed air are presented as lag ETOH per ml of rebreathed air
(~tg/mt). OF data are expressed as the average total counts for the
5-rain observation period for each of the four groups. Drug-associated responding, the concentrations of ETOH in rebreathed air
(randomized block design, Kirk 1968), and the response time data
(randomized block factorial design, Kirk 1968), were analyzed
using ANOVA. OF data were also analysed using ANOVAs (completely randomized design, Kirk 1968). For all the ANOVAs, post
hoc analyses were conducted with Tukey's HSD test, and the significance level set at P<0.05.
ii)

Results

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Drug discrimination learning

Acute tolerance to E T O H in DDL. Percentage of responding on the E T O H associated lever and concentrations o f E T O H in rebreathed air as a function o f dose
and time interval between injection and testing are
presented in Fig. 1. Section A of Fig. 1 shows the results
for the comparatively lower concentration of E T O H in
the organism; section B displays the outcome for the
relatively higher concentration of E T O H . Note that
within each concentration condition, the concentrations
of E T O H across doses and time intervals were intended
to be similar. F o u r separate statistical evaluations were
made, each pertaining to one of the four sections (upper
and lower, A and B) of the figure.
With regard to percentage of ETOH-related responding, significant main effects were observed for the treatment conditions [in section A, F(3,50)= 4.35, P < 0.009;
and in section B, F(2,34)= 8.37, P < 0 . 0 0 1 ] in both concentration conditions. The pairwise comparisons are
presented in the figure legend. N o significant differences
appeared when comparing doses which were below the
training dose. When test doses of E T O H below the training dose were c o m p a r e d with test doses higher than the
training dose within each concentration condition, significant differences occurred (for details see the figure
legend).
With respect to the concentrations o f E T O H in rebreathed air, no significant main effects were observed
for the treatment conditions [in section A, F(3,52) = 0.74,
P > 0 . 0 5 ; and in section B, F(2,34)=0.49, P>0.05].
Thus, approximately equal concentrations of E T O H
were obtained for the four first dose/time combinations
(section A, lower concentration condition), as well as for
the three last combinations (section B, higher concentration condition). A reduction of E T O H - a p p r o p r i a t e responding at equal concentrations would be in accordance with an interpretation of the occurrence of acute

m,m

Baseline performance. During discrimination maintenance sessions pertaining to periods of testing, the
animals averaged 95.3% and 95.2% correct first-choice
responding during the E T O H and saline training sessions, respectively. These averages are based on 622 and
648 observations, respectively.

. lOO

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DOSE
TIME

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10

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60

1.8 2.4
240 420

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10

O.OO
1.8 2.4 (g/kg)
180 360 (min)

1 A, B. Average percentage of ETOH-related responding (upper

sections), and mean concentrations of ETOH in rebreathed air
(lower sections), for the treatment conditions yielding lower (A), or
higher (B) ETOH concentrations. Y-axis, percentage of ETOHrelated responding (upper sections), and concentrations of ETOH
expressed as lag ETOH per ml rebreathed air (lower sections).
X-axis, doses of ETOH (g/kg), and injection to test intervals in min
(all graphs). Vertical lines represent SEM. In the upper graphs, the
following differences between means were significant (P < 0.05): a,
b differed from d (section A); g differed from e,f(section B). In the
iower graphs, neither of the ETOH concentrations for the first four
conditions (a, b, e and d), nor the concentrations for the last three
conditions (e, f and 9) differed significantly (P>0.05) from each
other
Fig.

tolerance when animals are exposed to doses higher than

those experienced before.

Response time in DDL. The response time data, i.e., the

time required to complete the first, or the remaining five
reinforcement ratios, are shown in Fig. 2; these data are
based on the same test occasions as those listed in Fig. 1.
Two separate statistical analyses ( R B F design, Kirk
1968) were performed, one for each concentration condition (section A and B). In comparisons between the low
concentration conditions (section A), a significant main
effect was observed when comparing the first with the
remaining five reinforcement ratios IF(l,118) = 11.66,
P < 0.0009]. The time required for the first reinforcement
ratio was longer than the mean of the remaining five
reinforcement ratios. The dose condition was also significant [F(3,118)=9.79, P<0.00001] indicating a doserelated increase in response time.
In comparisons between the high concentration
conditions (section B), a significant interaction was observed between treatment conditions and first versus the

210
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560 (m:n)

Fig. 2A, B. Average response-time for completion of the first reinforcement ratio (open histograms), and average response-time for
completion of the remaining five reinforcement ratios (striped histograms), for the treatment conditions yielding lower (A), or higher
(B) ETOH concentrations. Y-axis, average time in seconds for
completion of the first reinforcement ratio, or mean time for completion of the following five reinforcement ratios, respectively.
X-axis, doses of ETOH (g/kg), and injection to test intervals in minutes (both graphs). Vertical lines represent SEM. For A, none of
the differences between means were significant (P> 0.05). For B, b
differed from a, d, e and f, and c differed from a, dand e (P< 0.05).
[] Time to 1st SR+ ; [] mean after 1st SR+

remaining five reinforcement ratios [F(2,86)=10.74,

P < 0.0001]. Details of the post hoc pairwise comparisons
are presented in the legend of Fig. 2. The time required
to complete the first reinforcement ratio for the two high
dose conditions took longer than the time required for
the low dose condition. There were no significant differences between the means of the five remaining reinforcement ratios.

Acute tolerance in the open-field

The O F data disclosed an overall significant A N O V A
effect for the rearing behaviour [F(1,19) = 5.29,
P = 0.033]; the concentrations of E T O H in rebreathed air
between the two E T O H treatment conditions (N = 22)
were not significantly different [F(1,19) -- 1.45, P = 0.244].
The mean scores for rearing in the two E T O H groups,
and the corresponding concentrations of E T O H are
presented in Fig. 3. The animals tested during the
descending phase of the E T O H intoxication curve
(1.8 g/kg, 60 min post-inj ection) reared significantly more
than the animals tested during the ascending E T O H
concentration phase (1.5 g/kg, 10 min post-injection). N o
significant differences were observed for the other parameters examined (ambulation, grooming, latency, defecation, and urination). The results for rearing indicate the
occurrence of acute tolerance to E T O H for animals never
exposed to E T O H before the test.
Using a second group of experimentally naive animals ( N = 22), the possible differential influence of volume and injection-test interval were investigated in the
OF test. According to A N O V A , no significant difference
[F(1,20)=2.14, P = 0.159] occurred between the two saline groups with regard to rearing activity. The mean

2
0
DOSE
TIME

Fq

-0.20

r-t-q

o.lo

1.5
10

;
1.8
60

1.5
10

1.8
60

0,00
(g/kg)
(min)

Fig. 3. Effects of ETOH on rearing activity for drug-naive rats

exposed to an open-field OF test. Y-axis, mean rearing counts (left)
during the 5-min test, and the corresponding concentrations of
ETOH in rebreathed air (right). Vertical lines indicate SEM. X-axis,
doses of ETOH (g/kg) and injection to test intervals (min) for both
treatment groups. Significant differences were obtained between the
two groups with regard to rearing, but not for the concentrations
of ETOH

scores ( S E M ) for rearing in the two saline treated

groups were 24.0 3.8 (15 ml/kg, 10 rain post-injection),
and 30.82.7 (18 ml/kg, 60 min post-injection) counts
for the 5-min observation period. Thus, the difference in
rearing activity between the two E T O H treatment groups
cannot be explained by differences in the volumes administered, or the difference in time intervals between
injection and OF testing for the two E T O H - t r e a t e d
groups.

Discussion
A reduction of ETOH-related responding occurred
a m o n g the D D L rats when tested with doses higher than
the training dose, even though the breath E T O H concentrations were comparable. Doses o f E T O H lower
than the training dose did not produce such effects (Hiltunen et al. 1989; present results). The time to complete
the first reinforcement ratio was longer than the average
time for the five remaining reinforcement ratios in test
sessions. Additionally, after the highest dose of E T O H
tested, the time required to complete the tests were longer.
The finding that there was an attenuation in the
percentage of E T O H - a p p r o p r i a t e responding when examining doses higher than the training dose of E T O H ,
even though the concentrations of E T O H in breath was
similar, m a y be interpreted as supporting the occurrence
of acute tolerance to the discriminative stimulus effects
of E T O H . I f so, the degree of prior adaptation to E T O H
seems to be critical in the expression of acute tolerance.
F r o m the present results it is suggested that in the D D L
situation, as well as in other situations where the organism has previously been exposed to the drug, acute
tolerance is only seen when evaluating doses higher than
the ones previously experienced.
In support of such an account, it should firstly be
possible to see acute tolerance also in drug-naive animals.

211
Because most previous studies have measured ETOH
concentrations using venous and/or capillary blood,
these studies are not considered further (e.g. Ekman et
al. 1964; Wahlstr6m and Widerl6v 1971; Franks et al.
1974; Tullis et al. 1977; Campanelli et al. 1988). In the
present paper, acute tolerance to ETOH in drug-naive
rats was observed for rearing activity, i.e., the number of
times the animal stood on its hind feet, in the OF test.
It should be pointed out that this is the first time acute
tolerance has been demonstrated for this spontaneous
behaviour. Other OF behaviours such as ambulation,
grooming, etc. did not disclose a differential pattern
between the two time intervals. Further, LeBlanc et al.
(1975) demonstrated acute tolerance to ETOH for drugnaive rats in a moving belt procedure. Thus, acute
tolerance to ETOH can occur both with regard to unconditioned and conditioned behaviours in drug-naive animals.
Secondly, in ETOH pre-exposed animals it should be
possible to demonstrate acute tolerance with doses higher than, but not at, or below doses previously experienced. This was demonstrated for the drug (ETOH) discrimination animals. Although our study is the first
demonstration of the occurrence of acute tolerance to a
drug discriminative stimulus, rapid tolerance to the cueing effects of morphine has been described earlier (e.g.
Witkin et al. 1982). In that study, 1 day prior to performing dose generalization tests, 10 mg/kg morphine was
administered to the pigeons; the regular training dose
was 1 mg/kg. A shift to the right was seen after pretreatment with morphine. Such a change in the morphine
generalization gradient was not observed after pretreatments with pentobarbital, indicating that the
phenomenon was pharmacologically specific, i.e., drugclass specific. In studies reporting acute tolerance to
alcohol in humans (e.g. Radlow and Hurst 1985;
Haubenreisser and Vogel-Sprott 1987), the subjects have
usually been social drinkers exposed to rather high
doses of ETOH (0.6-1 g/kg), the drug being delivered
within a fairly short time period. In two studies concerning moderate and heavy alcohol drinkers (Moskowitz et
al. 1979; Portans et al. 1989), heavy drinkers appeared
less likely to demonstrate acute tolerance. In contrast,
Kaplan et al. (1985) found only limited evidence of acute
tolerance in humans maintained at a steady-state level of
ETOH concentrations for 6 h. However, as the six subjects differed in their weekly use of alcohol (54-338 g
absolute alcohol), it would have been interesting to know
it there were any indications of individual differences
with regard to the occurrence of acute tolerance.
There is an alternative explanation for the results
interpreted as acute tolerance in the present D D L work.
Administration of high doses of ETOH might have
changed the set point for ETOH-appropriate responding.
This change could have resulted from a phenomenon
similar to that of retraining the animal to attend to a
greater magnitude of the drug (ETOH) stimulus (Colpaert 1978). However, Wood et al. (1984) showed that
after the establishment of tolerance to the cocaine cue,
the sensitivity to baseline responding was recovered
spontaneously, i.e., without retraining the drug/nondrug

discrimination (see also Caul et al. 1989). The results of

Wood et al. (1984) were replicated and extended in a later
study by Wood and Emmett-Oglesby (1986) in which the
authors also reported cross-tolerance to amphetamine
but not to morphine. Such results seem not to favour the
hypothesis of a change in set point.
The self-reported subjective effects induced by drugs
in humans may be similar to the drug discriminative
stimulus effects as assessed in animals and men (Chait et
al. 1985, 1986a, b; Jobanson and Fischman 1989). In
humans, occurrence of acute tolerance to the subjective
effects of ETOH was investigated by Portans et al.
(1989), who compared the estimation of self-reported
peak intoxication level with the concentrations of ETOH
in breath, and by Radlow and Hurst (1985), who correlated breath ETOH concentrations with estimation of
magnitude of ETOH effects. Both studies gave evidence
for acute tolerance to the subjective effects of ETOH as
measured by self-reported degree of intoxication.
Different behaviours seem to be differentially susceptible to acute tolerance. Vogel-Sprott (1979) suggested
that acute tolerance to ETOH is more likely to occur for
cognitive functions as compared to more simple motor
functions. In the present study no acute tolerance was
seen for response time. It remains to be determinated if
the lack of effect also applies to other schedule-induced
performance measures.
The results of the present study may in part explain
why contradictory results have been reported in studies
of acute tolerance to ETOH and other drugs (e.g. see
discussion by Ellinwood et al. 1983). Because previous
exposure to ETOH seems to affect acute tolerance, a
control of the drinking history of the subjects should be
an extremely important factor in future investigations
concerning the phenomenon of acute tolerance.

Acknowledgements. We thank M.R. Kamkar for technical assistance and taking care of the animals, and Dr. D.A. Mathis for
improvements in the language. This study was supported by grants
from The Swedish Medical Research Council, The Bank of Sweden
Tercentenary Foundation, and The Swedish Alcohol Research
Fund.
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