ISSN EDICIÓN EN PAPEL: 0214-9915
2004. Vol. 16, nº 2, pp. 211-216
ALCOHOL TOLERANCE IN RATS SUBMITTED TO DIFFERENT PERIODS OF CHRONIC AND ACUTE ETHANOL INTAKE
Luis M. García-Moreno, Almudena Capilla, Olga García-Sánchez, Javier Luque, Kamila Senderek, Nélida M. Conejo and Jorge L. Arias
Universidad Complutense de Madrid, Technische Universität Berlín (Alemania) and Universidad de Oviedo
The development of tolerance to the effects of ethanol is not uniform and may vary according to the actual and previous pattern of consumption. In this experiment we assessed body temperature and the recovery of two reflexes after a high dose of ethanol in rats submitted to chronic and acute ethanol consumption. Animals were previously submitted to chronic or acute alcohol consumption from postnatal day 21 until postnatal days 56 and 84. On the testing days, the animals received a single dose of 25% ethanol (5 g/kg, i.p.) or the same amount of saline solution. The results showed that animals were affected in the day 56 to a greater extent than in the day 84 by chronic heavy consumption of ethanol solution. With moderate and acute ethanol consumption, the 56-day-old animals developed greater tolerance. However, tolerance was not developed for the motor-impairing effects, since all groups required a long time to recover reflexes.
Tolerancia al alcohol en ratas sometidas a diferentes períodos de consumo agudo y crónico de etanol. El desarrollo de tolerancia a los efectos del alcohol no es uniforme, y suele variar según el patrón de consumo previo y actual. En este trabajo se evaluó la temperatura corporal y el tiempo de recuperación de dos reflejos tras el consumo crónico y agudo de elevadas dosis de etanol. Previamente, los animales bebieron alcohol de forma crónica o aguda desde los 21 hasta los 56 y 84 días de edad. Durante los días de evaluación, los animales recibieron una única dosis de etanol al 25% (5 g/kg, i.p.), o la misma cantidad de solución salina. Los resultados mostraron una mayor afectación a los 56 días de consumo crónico elevado de etanol respecto a los 84 días. Con un consumo moderado o agudo de etanol, los animales de 56 días desarrollaron una mayor tolerancia. Sin embargo, esta tolerancia no se observó en cuanto a los déficits motores, dado que todos los grupos necesitaron un largo período de tiempo para recuperar los reflejos.
Fecha recepción: 3-9-03 • Fecha aceptación: 16-12-03
Correspondencia: Luis M. García-Moreno
Facultad de Educación
Universidad Complutense de Madrid
28040 Madrid (Spain)
Alcoholism is a human disorder that causes a great number of
social, family and psychological problems in our society. Traffic accidents
are the main cause of death among young people and many of these have been caused
by high alcohol consumption. Impaired judgment and increased reaction time are
most often cited as the causes of alcohol-related traffic accidents (Gómez
Fraguela, Luengo Martín and Romero Triñanes, 2002; Naranjo and
Bremner, 1993). Laboratory psychopharmacologic studies indicate that doses of
ethanol up to 1 g/Kg are associated with a general slowing down of psychomotor
and cognitive performance such as reduced information-processing capacity or
impaired tracking performance in real and simulated driving tasks (Hindmarch,
Kerr and Sherwood, 1991; Maylor and Rabbitt, 1993). Nowadays, young people drink
alcohol at an early age and consume large amounts in very short periods of time.
Most people begin drinking in adolescence and many recent studies have indicated
that adolescence may represent a period of development of great sensitivity
to ethanol and that, in this period, behavioral and neuronal aspects are more
affected than in adulthood (Rodríguez Franco, Padilla Muñoz, Caballero
and Rodríguez, 2002; De Bellis et al., 2000; Acheson, Richardson and
Swartzwelder, 1999; Pyapali, Turner, Wilson and Swartzwelder, 1999; Swartzwelder,
Richardson, Markwiese-Foerch, Wilson and Little, 1998; Markwiese, Acheson, Levin,
Wilson and Swartzwelder, 1998; Swartzwelder, Wilson and Tayyeb, 1995).
One component of alcoholism that is commonly studied is the
development of alcohol tolerance after chronic or acute alcohol consumption.
According to DSM-IV (American Psychiatryc Association, 1994), alcohol tolerance
is the decrease in ethanol effects with regular consumption of the same dose
or the necessity to drink more alcohol to experience the same effects. However,
the development of tolerance is not uniform and the effects of ethanol decrease
to different extents and in different time periods. Previous studies in adult
rats have shown that tolerance to the effect of ethanol on body temperature
develops prior to tolerance to motor-impairing effects (Pohorecky, Brick and
Carpenter, 1986). One of the characteristic response to administration of moderate
to high doses of ethanol is a decrease in body temperature. Ethanol-induced
hypothermia has been utilized extensively in the ethanol research field for
several decades as a measure of ethanol’s acute effects, and as a model system
for the study of ethanol tolerance (Crabbe, Feller, Terda and Merrill, 1990;
Crabbe, Janovsky, Young, Kosobud, Stack and Rigter, 1982).
Many models of alcoholism use chronic self-administration to
evaluate the effects of intake whereas other models prefer acute administration
to determine the punctual effects of ethanol. However, many social drinkers,
especially the younger ones, present two different drinking patterns: chronic
regular consumption and, occasionally, acute intake of higher doses. Moreover,
the amount of ethanol consumed chronically and the pattern of intake may determine
the intensity of effects on drinkers. For this reason, the present study was
designed to determine the alcohol tolerance to body temperature and motor-impairment
effects of ethanol in rats submitted to chronic and acute alcohol consumption
after a high dose of ethanol that may be considered as a high acute intake.
We assessed body temperature and the recovery of two reflexes after a high dose
of ethanol in rats submitted to acute and chronic alcohol consumption with two
alcoholic solutions during two periods of time.
Material and methods
A total of 128 male Wistar rats, weighing 240-305 g were used
in the experiment. They were housed individually in a temperature- and humidity-controlled
environment with a 12 hours light/dark cycle (8:00 - 20:00) and the ambient
temperature was 24±3ºC. During the experiment, animals had free access to food
and liquid. Rats were randomly assigned to one of four experimental groups.
(I) Control rats, animals without experimental manipulation (CTR), (II) rats
chronically administered a high dose of ethanol (20%, v/v) (ALCH), (III) rats
receiving chronic treatment with a moderate dose of ethanol (10%, v/v) (ALCM),
and (IV) rats submitted to acute intake of ethanol (ALCA). Each of these groups
was then divided into two subgroups, one of which was evaluated on postnatal
day 56 (PD-56) and the other group on postnatal day 84 (PD-84). Then, four groups
of sixteen animals were evaluated when the animals submitted to chronic alcohol
intake reached the highest dose of ethanol solution (10% or 20% in the PD-56),
and the remaining four groups were studied four weeks later.
Alcohol consumption procedure
Alcohol-treated rats (ALCH and ALCM) had free access to an
aqueous ethanol solution (Panreac, Barcelona, Spain) as the only available liquid
source from 21 days old to the end of experiment (postnatal days 56 and 84).
In ALCH group, the administration was gradual, starting with 2% (v/v) in the
first week after the 21st postnatal day with a doubling dosage each week until
it reached the 16% (v/v). In the following week, the dose was 20% (v/v) until
the end of the experiment. In the ALCM group, the administration was 2%, 4%,
6%, 8% each week, and 10% until the end of the experiment. Animals first received
the ethanol solution at postnatal day 21 to avoid rejection due to the taste
of ethanol (Capretta, Petersik and Stwart, 1975) and so they would consume similar
amounts of liquid as control animals (Table 1). This model provokes the progressive
alcohol consumption of the animals and produced hepatic lesions in the animals
after nine months similar to those observed in alcoholic liver disease in humans
(García-Moreno, Corcuera, Conejo, Martín, Gómez and Alonso,
1998). Finally, animals from ALCA group received 2 gr/Kg of ethanol in saline
solution (25%, v/v) once per week by intraperitoneal injection (IP). This procedure
does not cause dehydration or loss of electrolytes in animals (Tang and Falk,
1986). On the day of the evaluation (PD-56 or PD-84) the animals received
a single dose of ethanol solution administered intraperitoneally (5 g/Kg, 25%
sol. v/v) or the same amount of saline solution to evaluate its effects on the
animals’ body temperature and motor behaviour. We used this dose and route of
administration because they produced sedation (Swartzwelder et al., 1998). We
observed that the most frequent dose range used in similar experiments ranges
between 1.5 and 3.2 g/Kg (Khanna, Kalant, Weiner and Shah, 1992; Lomax, Bajorek,
Chesarek and Chafee, 1980); however, we also found works that used higher doses
(Swartzwelder et al., 1998; Le, Khanna and Kalant, 1984). We opted for a high
dose to ensure a sedative effect and also because we thought that a higher dose
would facilitate identification of differences in previous consumption pattern.
Body temperature (expressed in degrees centigrade)
From three days before evaluation, we recorded daily the colonic
temperatures of all rats in the morning (between 9’00 and 10’00 a.m.) using
a digital thermometer OMRON MC-38 (Omron Matsusaka Co Ltd. Japan). On the testing
day, we also measured the colonic temperatures of animals immediately before
they received the intraperitoneally injection of ethanol. After this, the colonic
temperatures were measured again 90 and 180 minutes after the IP injection to
determine possible temperature changes.
We also tested two righting reflexes every 15 minutes after
IP ethanol injection until the animals reached the criterion of reflex recovery.
First we evaluated the floor-righting reflex, the ability of each animal to
right itself (all legs on the floor) within 3 seconds after being placed on
its back. Reflex was recovered when the animal successfully righted itself twice
consecutively. We then evaluated the fall-righting reflex. When the rat is dropped
upside down from a 40 cm height onto a soft surface, it turns during the fall
and lands on all four legs. This reflex was recovered when the animal landed
correctly twice consecutively.
Changes in body temperature after IP (expressed in degrees
centigrade) and the time spent to recover reflexes (expressed in minutes) were
recorded. Statistical analyses corresponded to a three-way analysis of variance
to assess the significance of the duration of intake (Period, PD-56 or
PD-84), the pattern of alcohol intake (Group, acute or moderate and high
chronic) and IP injection (IP, ethanol or saline). To establish differences
between the groups the Student-Newman-Keuls Method was used.
In summary, the animals consumed alcohol chronically or in
an acute manner over five or nine weeks. On the day of the evaluation the animal’s
body temperature was measured and then they received an intraperitoneal injection
of ethanol. After, the body temperature was measured again and two types of
reflex behaviour were evaluated to see if the animals had developed tolerance
to the reduction in body temperature and alteration in the motor behaviour caused
Table 1 shows the changes in body temperature (Mean ±SE) of
all the groups of animals at 90 and 180 minutes after the IP. We performed the
statistical analysis with the values measured at 90 minutes because the behaviour
of the data at 180’ was very similar to those obtained at 90’, then, statistical
differences were similar in both periods (Fig. 1 and 2). The Three-way ANOVA
showed significant effects of the factors group (F3,112= 15.52, P<0.001),
IP (F1,112= 266.40, P<0.001) and the interaction between them (F3,112=
16.48, P<0.001). We also found a significant interaction among the three
variables (F3,112= 6.07, P<0.001), and between the variables period
and group (F3,112= 5.58, P= 0.001) but not between period and
IP. The animals that received saline IP exhibited little change in body
temperature in both the PD-56 and PD-84 groups. However, the animals administered
ethanol IP showed great variations in body temperature and with differences
among all the groups. In the PD-56 animals, the greatest variations in body
temperature were found in the CTR and ALCH groups that differed significantly
from the ALCM and ALCA groups (P<0.05) (Figure 1). No differences were observed
between ALCM and ALCA or between CTR and ALCH. This means that the animals from
the ALCM and ALCA groups presented the highest tolerance to acute ethanol administration.
In contrast, as expected, animals from the CTR group exhibited a low tolerance
but, surprisingly, this was similar to the tolerance level observed in animals
that received chronic alcohol consumption with the high concentration solution.
The CTR, ALCM and ALCA groups of PD-84 animals exhibited a similar behavior
to the PD-56 ones. However, animals from the ALCH group presented an increased
tolerance level and reached a similar level as the other alcoholic groups (Figure
2). With the PD-84 animals, no significant differences were observed among alcoholic
groups but all differed significantly from the CTR group (P<0.05).
With regard to floor righting reflex, we found significant
effects of the factors group (F3,112= 9.67, P<0.001), IP (F1,112=
852.61, P<0.001) and the interaction between them (F3,112= 9.67, P<0.001).
All the animals that received saline IP reached the criterion of recovery at
the first test (15’). However, the PD-56 animals that received ethanol IP needed
significantly more time to recover the reflex (P<0.05). Among these animals,
the ALCH group required more time than the other groups (P<0.05)(Figure 3).
In the PD-84 animals, no significant differences were found among ethanol IP
groups but these differed significantly from saline IP groups (P<0.05) that
reached the criterion at 15’. In the fall righting reflex, only the IP factor
had a significant effect (F1,112= 1.47, P<0.001). Both the PD-56 and PD-84
animals that received saline IP reached the criterion in the first test, whereas
the animals with ethanol IP needed significantly more time to do it (P<0.05).
In this case, no differences were found among alcoholic and control groups (Figure
4) of animals that received ethanol IP.
Acute consumption of large amounts of alcohol causes hypothermia
and loss of some reflexes among other effects. In our experiment, we found both
effects but only alcoholic animals showed tolerance to hypothermia. The ability
to recover reflexes after ethanol IP was greatly improved in all groups, both
alcoholic and control. Those receiving saline IP reached the criteria in the
first test fifteen minutes after the injection. However, those receiving ethanol
IP required significantly more time. Several authors have shown that moderate
doses of ethanol can alter the air righting reflex (Tracy, Wayner and Armstrong,
1999; Tracy and Wayner, 1998). The PD-56 animals from the ALCH group needed
more time to recover the floor righting reflex than the other groups. However,
all PD-84 groups took a similar length of time to achieve this. For the fall
righting reflex, all groups of PD-56 and PD-84 animals required a similar time.
The air righting reflex is a more complex task than the straightening reflex
and is acquired postnatally while straightening is present, although imperfectly,
at birth (Pellis, Pellis and Whishaw, 1996; Pellis and Pellis, 1994; Pellis,
Pellis and Nelson, 1992).
With our data we can deduce that these animals did not exhibit
alcohol tolerance and that PD-56 animals were more impaired than adults ones
by acute intake after chronic high alcohol consumption. A probably explanation
is that the dose administered was too high (5 gr/Kg) and that with a lower dose
we could found significant differences in developing tolerance among groups.
However, all alcoholic animals developed different degrees of alcohol tolerance
to hypothermia after acute consumption. These results agree with other studies
that found differences in developing tolerance to hypothermia or sedative effects
of ethanol (Swartzwelder el al., 1998; Pohorecky el al., 1986).
The PD-56 animals that consumed 10% ethanol chronically or
those that consumed acutely developed a great tolerance to ethanol-induced hypothermia.
However, the PD-56 animals that consumed 20% ethanol chronically did not exhibit
tolerance and the ethanol-induced hypothermia was similar to that of the animals
from the control group. The PD-84 animals from the CTR, ALCM and ALCA groups
showed a similar level of hypothermia to the PD-56 ones. However, the PD-84
animals that received 20% ethanol (ALCH) showed less hypothermia than the young
ones. This could mean that with this dose of chronic ethanol consumption the
PD-84 animals developed alcohol tolerance after acute consumption whereas the
PD-56 animals did not. During adolescence, alcohol intake may cause development
of higher and faster tolerance than in adulthood (Swartzwelder el al., 1998;
Pohorecky et al., 1986). However, the period of alcohol intake before the test
could be an important factor since the young animals, assessed on postnatal
day 56, consumed alcohol for five weeks whereas the adult animals, assessed
on PD-84, consumed it for nine weeks.
Long-term alcohol dependence, as a consequence of alcoholic
tolerance, results in neuronal adaptation that probably contributes to ethanol
withdrawal-induced central nervous system excitability and, potentially, neurotoxicity.
A possible explanation for the lower tolerance in ALCH PD-56 animals is that,
with a high ethanol intake, the neurons need more time to develop the adaptation
process but that this neuroadaptation would be possible with lower amounts of
ethanol. Ethanol has potent effects on both excitatory and inhibitory neurotransmitter
systems, one of which is glutamate. Chronic ethanol exposure leads to an up-regulation
of NMDA receptors (Grant and Lovinger, 1995) and excitotoxicity occurs following
excessive excitation of neurons through glutamate receptors.
The participation of NMDA receptor in tolerance development
has been clearly demonstrated (Khanna, Shah and Chau, 1997; Khanna, Chau and
Shah, 1996) and the pharmacological activity of the NMDA receptor may be influenced
by the history of alcohol consumption (Neznanova, Blokhina, Sukhotina and Bespalov,
2000). Cheema et al. (2000) found that ethanol induces a susceptibility to apoptotic
signals at low doses in the developing cerebral cortex, but ethanol itself specifically
induces apoptosis at higher doses. Moreover, studies of Germani et al. (1999)
suggest that chronic exposure to ethanol can influence central nervous system
plasticity during development. According to these authors, low doses of ethanol
may enhance neural plasticity perhaps via an increased efficacy of neurotrophic
factors, whereas higher doses may negatively affect neural development also
by means of the impairment of the expression of the neurotrophic factors (Germani
el al., 1999). Animals from the ALCH group could have suffered from a higher
neurotoxicity that would make difficult the neuroadaptation that can occur in
animals from the ALCM and ALCA groups with lower alcohol consumption. Signs
of severe toxicity occur at lower blood alcohol concentrations in young teenagers
than in adults whereas the elimination rate of ethanol is similar in both groups
(Lamminpa, 1995). Glutamate-mediated excitoxicity has been divided into two
components: a rapid component associated with osmotic swelling and often immediate
neuronal death, and a delayed component that occurs as a progressive degenerative
process over a period of hours to days. Both processes are related to excess
accumulation of calcium (Meldrum and Gartwaite, 1990; Olney, 1990; Orrenius,
McConkey, Bellomo and Nicotera, 1989). Chronic ethanol consumption induces an
adaptive supersensibility of NMDA receptors that can increase excitoxicity (Nagy,
Muller and Laszlo, 2001; Crews, Steck, Chandler, Yu and Day, 1998; Smothers,
Mrotek and Lovinger, 1997). It is possible that low ethanol intake will produce
changes in synaptic plasticity that lead to the development of alcohol tolerance
whereas high ethanol intake could lead to excitotoxicity and neuronal death.
The answer to this question must also be found in the GABAA
receptor system since the activity of this receptor, together with the NMDA,
plays an important role in both the acute as well as chronic effects of ethanol
(Steffensen, Nie, Criado and Siggins, 2000; Grobin, Matthews, Devaud and Morrow,
1998). Both NMDA and GABAA receptors are composed of multiple subunit proteins,
which are thought to assemble as hetero-pentameric structures that exhibit distinct
properties depending upon the particular subunit composition. Chronic ethanol
intake leads to the development of ethanol tolerance and dependence that is
associated with a decrease in GABAergic and an increase in glutamatergic function
but these effects vary across the brain (Chandler, Harris and Crews, 1998; Devaud,
Moreover, prolonged exposure to alcohol was found, with a similar
model to this one (20% final alcohol) to produce a decline in the response of
the hypothalamus-hypophysary-adrenal axis (HPA), related with the development
of tolerance to ethanol effects (Silva, Paula-Barbosa and Madeira, 2002). Given
that the HPA axis still follows a maturation process after 21 days (Vazquez,
1998), could temporarily alter the functioning of the HPA axis and this would
explain that young animals could be more sensitive to the sedative effects of
alcohol and would not develop tolerance until the adult age. On the other hand,
the handling itself (specifically, repeated introduction of the rectal thermometer
and immobilisation of the animal) can interact with the effects of alcohol,
altering the hypothermia (Peris and Cunningham, 1987).
Animals from the ALCA group may present a more conditioned
tolerance since the changes in hypothermia are less pronounced than in the ALCM
group. This is because these animals always received the ethanol IP on the same
day and in the same place. Several studies have shown that animals submitted
to regular ethanol injections developed tolerance to a challenge injection when
the process was carried out in the same place, whereas animals submitted to
the same procedure did not when they were assessed in a different room (Duncan,
Alici and Woodward, 2000; Crowell, Hinson and Siegel, 1981). However, this aspect
requires further research in order to elucidate the characteristics of the conditioning
process that underlies alcohol tolerance.
In our experiment, we have simulated different patterns of
alcohol consumption, some of which are very common among human people. These
data support the idea that young people are very sensitive to ethanol effects
and that tolerance to the different effects of ethanol develops at different
times. Moreover, alcoholic tolerance prior to alcoholic dependence can be developed
a very short periods of alcohol consumption. Apart from individual differences,
the history of alcohol consumption may determine, in part, the effect of acute
consumption. We consider that young people should receive appropriate information
about the risk of alcohol consumption.
This work was supported by grants PR78/02-10972 (Complutense
University), MCYT BSO 2001-2757 (Ministry of Science and Technology, Spain)
and PR-01-GE-2 (Principado de Asturias, Spain).
Acheson, A.K., Richardson, R. and Swartzwelder, H.A. (1999). Developmental changes in seizure susceptibility during ethanol withdrawal. Alcohol, 18: 23-26.
American Psychiatryc Association, (1994). Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition (DSM-IV). American Psychiatryc Association. Washington, DC.
Capretta, P.J., Petersik, J.T. and Stwart, D.J. (1975). Acceptance of novel flavors is increased after early experience of diverse tastes. Nature, 254, 689-691.
Chandler, L.J., Harris, R.A. and Crews, F.T. (1998). Ethanol tolerance and synaptic plasticity. Trends in Pharmacological Sciences, 19, 491-495.
Cheema, Z.F., West, J.R. and Miranda, R.C. (2000). Ethanol induces Fas/Apo [apoptosis]-1 nRNA and cell suicide in the developing cerebral cortex. Alcoholism Clinical and Experimental Research, 24, 535-543.
Crabbe, J.C., Feller, D.J., Terda, E.S. and Merrill, C.D. (1990). Genetic components of ethanol responses. Alcohol, 7, 245-249.
Crabbe, J.C., Janovsky, J.S., Young, E.R., Kosobud, A., Stack, J. and Rigter, H. (1982). Tolerance to ethanol hypothermia in imbred mice: genotypic correlations with behavioral responses. Alcoholism Clinical and Experimental Research, 6, 446-458.
Crews, F.T., Steck, J.C., Chandler, L.J., Yu, C.J. and Day, A. (1998). Ethanol, stroke, brain damage, and excitotoxicity. Pharmacology Biochemistry and Behavior, 59, 981-991.
Crowell, C.R., Hinson, R.E. and Siegel, S. (1981). The role of conditional drug response in tolerance to the hypothermic effects of ethanol. Psychopharmacology, 73, 51- 54.
De Bellis, M.D., Clark, D.B., Beers, S.R., Soloff, P.H., Boring, A.M., Hall, J., Kersh, A. and Keshavan, M.S. (2000). Hippocampal volume in adolescent-onset alcohol use disorders. The American Journal of Psychiatry, 157, 737-744.
Devaud, L.L. (2001). Ethanol dependence has limited effects on GABA or glutamate transporters in rat brain. Alcoholism Clinical and Experimental Research, 25, 606-611.
Duncan, P.M., Alici, T. and Woodward, J.D. (2000). Conditioned compensatory response to ethanol as indicated by locomotor activity in rats. Behavioural Pharmacology, 11, 395-402.
García-Moreno, L.M., Corcuera, M.T., Conejo, N.M., Martín, F.R., Gómez, M. and Alonso, M.J. (1998). Alteraciones hepáticas en un modelo de alcoholismo en ratas. Anual de Medicina Interna, 15, 241-245.
Germani, E., Suck, M.L.T., Di Giulio, A.M. and Gorio, A. (1999). Perinatal supplementation of low doses of ethanol enhances 5-HT restoration in the central nervous system. Journal of Neuroscience Research, 58, 449-455.
Gómez Fraguela, J.A., Luengo Martín, A. and Romero Triñanes, E. (2002). Prevención del consumo de drogas en la escuela: cuatro años de seguimiento de un programa. Psicothema, 14(4), 685-692.
Grant, K.A. and Lovinger, D.M. (1995). Cellular and behavioral neurobiology of alcohol: receptor-mediated neuronal processes. Clinical Neuroscience, 3, 155-164.
Grobin, A.C., Matthews, D.B., Devaud, L.L. and Morrow, A.L. (1998). The role of GABA(A) receptors in the acute and chronic effects of ethanol. Psychopharmacology, 139, 2-19.
Hindmarch, I., Kerr, J.S. and Sherwood, N. (1991). The effects of alcohol and other drugs on psychomotor performance and cognitive function. Alcohol Alcohol, 26, 71.
Khanna, J.M., Chau, A. and Shah, G. (1996). Characterization of the phenomenon of rapid tolerance to ethanol. Alcohol, 13, 621-628.
Khanna, J.M., Kalant, H., Weiner, J. and Shah, G. (1992). Rapid tolerance and cross-tolerance as predictors of chronic tolerance and cross-tolerance. Pharmacology Biochemistry and Behavior, 41, 355-360.
Khanna, J.M., Shah, G. and Chau, A. (1997). Effect of NMDA antagonists on rapid tolerance to ethanol under two different testing paradigms. Pharmacology Biochemistry and Behavior, 57, 693-697.
Lamminpa, A. (1995). Alcohol intoxication in childhood and adolescence. Alcohol Alcohol, 30, 5-12.
Le, A.D., Khanna, J.M. and Kalant, H. (1984). Effect of treatment dose and test system on the development of ethanol tolerance and physical dependence. Alcohol, 1: 447-451.
Lomax, P., Bajorek, J.G., Chesarek, W.A. and Chafee, R.R. (1980). Ethanol-induced hypothermia in the rat. Pharmacology, 21, 288-294.
Markwiese, B.J., Acheson, S.K., Levin, E.D., Wilson, W.A. and Swartzwelder, H.S. (1998). Differential effects of ethanol on memory in adolescent and adult rats. Alcoholism Clinical and Experimental Research, 22, 416-421.
Maylor, E.A. and Rabbitt, P.M.A. (1993). Alcohol, reaction time and memory: a meta-analisys. British Journal of Psychology, 84, 301-317.
Meldrum, B. and Gartwaite, J. (1990). Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends in Pharmacological Sciences, 11, 379-387.
Nagy, J., Muller, F. and Laszlo, L. (2001). Cytotoxic effect of ethanol-withdrawal on primary cultures of cortical neurons. Drug and Alcohol Dependence, 61, 155-162.
Naranjo, C.A. and Bremner, K.E. (1993). Behavioural correlates of alcohol intoxication. Addiction, 88, 25-35.
Neznanova, O.N., Blokhina, E.A., Sukhotina, I.A. and Bespalov, A.Y. (2000). Motor impairment produced by ethanol and site-selective NMDA receptor antagonists in micetolerance and cross-tolerance. Alcohol, 20, 31-36.
Olney, J.W. (1990). Excitotoxin-mediated neuron death in youth and old age. Progress in Brain Research, 86, 37-51.
Orrenius, S., McConkey, D.J., Bellomo, G. and Nicotera, P. (1989). Role of Ca2+ in toxic cell killing. Trends in Pharmacological Sciences, 10, 281-285.
Pellis, S.M. and Pellis, V.C. (1994). Development of righting when falling from a bipedal standing posture: evidence for the dissociation of dynamic and static righiting reflexes in rats. Physiology and Behavior, 56, 659-663.
Pellis, S.M., Pellis, V.C. and Nelson, J.E. (1992). The development of righting reflexes in the pouch young of the marsupial Dasyurus Hallucatus. Developmental Psychobiology, 25, 105-125.
Pellis, S.M., Pellis, V.C. and Whishaw, I.Q. (1996). Visual modulation of air righting by rats involves calculation of time-to-impact, but does not require the detection of the looming stimulus of the approaching ground. Behavioural Brain Research, 74, 207-211.
Peris, J, and Cunningham, C.L. (1987). Stress enhances the development of tolerance to the hypothermic effect of ethanol. Alcohol and Drug Research, 7, 187-193.
Pohorecky, L.A., Brick, J. and Carpenter, J.A. (1986). Assessment of the development of tolerance to ethanol using multiple measures. Alcoholism Clinical and Experimental Research, 10, 616-622.
Pyapali, G.K., Turner, D.A., Wilson, W.A. and Swartzwelder, H.S. (1999). Age and dose-dependent effects of ethanol on the induction of hippocampal long-term potentiation. Alcohol, 19, 107-111.
Rodríguez Franco, L., Padilla Muñoz, E., Caballero, R. and Rodríguez, J. (2002). Ansiedad en hijos de padres alcohólicos en tratamiento. Psicothema, 14(1), 9-18.
Silva, S.M., Paula-Barbosa, M.M. and Madeira, M.D. (2002). Prolonged alcohol intake leads to reversible depression of corticotropin-releasing hormone and vasopressin immunoreactivity and mRNA levels in the parvocellular neurons of the paraventricular nucleus. Brain Research, 954, 82-93.
Smothers, C.T., Mrotek, J.J. and Lovinger, D.M. (1997). Chronic ethanol exposure leads to a selective enhancement of N-methyl-D-aspartate receptor function in cultured hippocampal neurons. Journal of Pharmacology and Experimental Therapeutics, 283, 1214-1222.
Steffensen, S.C., Nie, Z., Criado, J.R. and Siggins, G.R. (2000). Ethanol inhibition of N-metyl-D-aspartate receptors involves presynaptic g-amynobutiric acid (B) receptors. Journal of Pharmacology and Experimental Therapeutics, 294, 637-697.
Swartzwelder, H.S., Richardson, R.C., Markwiese-Foerch, B., Wilson, W.A and Little, P.J. (1998). Developmental differences in the acquisition of tolerance to ethanol. Alcohol, 4, 311-314.
Swartzwelder, H.S., Wilson, W.A. and Tayyeb, M.Y. (1995). Age-dependent inhibition of long-term potentiation by ethanol in inmature vs mature hippocampus. Alcoholism Clinical and Experimental Research, 19, 1480-1485.
Tang, M. and Falk, J.L. (1986). Chronic alcohol dependence and water-electrolyte status. Alcohol, 3, 33-37.
Tracy, H.A. and Wayner, M.J. (1998). Losartan blocks diazepam and ethanol effects on air righting. Alcohol, 16, 93-99.
Tracy, H.A., Wayner, M.J. and Armstrong, D.L. (1999). Nicotine blocks ethanol and diazepam impairment of air righting and ethanol impairment of maze performance. Alcohol, 18, 123-130.
Vazquez, D.M. (1998). Stress and the developing limbic-hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology, 23, 663-700.