HIGH ETHANOL PREFERRING RATS FAIL TO SHOW DEPENDENCE FOLLOWING SHORT- OR LONG-TERM ETHANOL EXPOSURE

Pierre Mormede1, Anthony Colas1 and Byron C. Jones2,*

1 Laboratoire de Neurogénétique et Stress UMR-1243-INRA INSERM U471, Université Victor Segalen Bordeaux 2, Institut François Magendie, Bordeaux, France and 2 Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, USA

* Author to whom correspondence should be addressed at: Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA 16802-6508, USA. Tel.: +814 863 0167; Fax: +814 863 7525; E-mail: bcj1{at}email.psu.edu

(Received 7 March 2003; in revised form 19 November 2003; accepted 25 November 2003)


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: The high ethanol preferring (HEP) rat shows high total ethanol consumption, high spontaneous activity and high consumption of novel tastants. Because these animals consume large quantities of ethanol daily, we sought to determine whether they could become alcohol-dependent by repeated exposures of varying lengths and withdrawals of alcohol, both in short- and long-term ethanol exposure. Methods: Male and female HEP rats were subjected to short (14 days) or long (20 weeks) exposure to 10% ethanol in a two choice (vs. water) test. During the short- and long-term ethanol exposures, the animals were repeatedly deprived of ethanol for 5 days followed by reinstatement of the two-choice test. Moreover, pharmacological interventions (morphine and naltrexone), adulteration of ethanol by quinine and addition of saccharine to water were applied to test the lability of a possible alcohol deprivation effect. Results: In every case, deprivation produced a high initial intake of ethanol that lasted 0.5 h, but thereafter no significant increase in alcohol consumption, compared to predeprivation. Even after several months of continuous drinking of large amounts of ethanol, the animals were sensitive to adulteration of the alcohol solution by quinine, that reduced the intake, and still preferred a saccharine solution when presented as a free choice with the alcohol solution. Pretreatment with morphine increased ethanol consumption in the first 0.5 h following deprivation, whereas naltrexone reduced it. Conclusions: Taste reinforcement is probably a major component of alcohol drinking by the HEP rats, and that while these rats consume large quantities of ethanol both in the short- and long-term, they do not show a robust alcohol deprivation effect.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Genetically defined animal models of disease are valuable sources of information about disease processes and mechanisms as they might be observed in humans. Nevertheless, the majority, if not all of these models have limitations, primarily in terms of the breadth of the multiple characteristics of the disease they encompass. Alcohol-related disorders are no exception. Thus, most models focus on one or two aspects of alcoholism, for example initial consumption, chronic consumption, tolerance and sensitivity to alcohol. This specific caveat was described by McClearn (1979)Go, who used the term ‘simulacra’ to indicate the restricted, if precisely defined, phenotypic criteria characteristic of the several genetically defined rodent models of alcohol-related disorders. Nevertheless, Cicero (1979)Go provided six criteria that should be met for an all-encompassing animal model of alcoholism. They are as follows. (1) The animal should self-administer alcohol orally. (2) The amount of alcohol ingested should be pharmacologically significant, that is the amount ingested should approach or exceed the limit of metabolism and elevate blood alcohol concentrations to pharmacologically significant levels. (3) Alcohol should be consumed primarily for its post-ingestive pharmacological effects and not solely for its caloric value, taste or smell. (4) Ethanol should be positively reinforcing, and animals should be willing to work and overcome obstacles to obtain alcohol. (5) Both metabolic and functional tolerance to ethanol should develop after a period of chronic consumption. (6) Physical signs of dependence on ethanol should develop following alcohol withdrawal after a period of chronic consumption.

Our group and others have shown that the HEP rats meet the first two criteria (Myers et al., 1998Go; Terenina-Rigaldie et al., 2003bGo); however, the other criteria have been largely unexplored. We have shown previously that the males of this line consume between 3 and 4 g/kg/day of 10% v/v ethanol and females 6–8 g/kg/day in a two choice (vs. water) test. Moreover, both sexes show an increase in daily consumption over a 14-day test period. Thus, we were interested to know whether these animals would become dependent on ethanol, either in the short run or following prolonged exposure.

Exactly how to define dependence is problematic. One could use indices of malaise, as in the case of seizures during withdrawal induced by handling (Buck et al., 1997Go), but this index shows only the consequences of abrupt cessation of ethanol exposure. A better index might be to show increased alcohol-seeking and consumption following a period of withdrawal (i.e. the alcohol deprivation effect; ADE), during which the acute effects of withdrawal would have passed (Sinclair and Senter, 1967Go). These signs of increased craving constitute a key element of changes in craving necessary to model human relapse in animals (Li, 2000Go). Indeed, other researchers have demonstrated indices of increased ethanol craving in chronically exposed animals subjected to single and/or repeated periods of deprivation (Hölter et al., 1998Go; 2000Go; Rimondini et al., 2002Go). Finally, the question of whether the increased drug-seeking is based on previous pharmacological and pathophysiological (i.e. pharmacodynamic) changes must be addressed.

We designed a series of studies to determine whether the HEP rats would show increased ethanol consumption (i.e. ADE) following short- or long-term two-choice (vs. water) exposure and if so, whether the phenotype is truly an index of dependence on ethanol.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals
All of the animals used in the experiments described below were HEP rats from the seventh or eighth generation since derivation, born in our laboratory from breeders generously supplied by Dr Robert D. Myers (East Carolina University, Greenville, NC, USA). The derivation of these animals is described elsewhere (Myers et al., 1998Go) and involved the identification of high ethanol consuming Sprague Dawley rats and interbreeding them with the ethanol-preferring (P) rats derived at Indiana University (Li et al., 1993Go). For all experiments, both male and female rats were used, primarily because the females, like other rodents, consume significantly more ethanol than do the males (Jones and Whitfield, 1995Go). Housing was in the Institut François Magendie vivarium with temperature maintained at 21 ± 1°C, relative humidity at 65–75% and a light:dark cycle of 12 h with lights on at 06.00 hours. Food was available ad libitum and fluids consisting of water and/or solutions of ethanol and saccharine always available. All animals were weighed twice weekly. All procedures used in these studies were in compliance with the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, 18 March, 1986.

Drugs
For all of the ethanol-consumption procedures, 95% v/v ethanol was used to prepare the various concentrations used (see below). Morphine as the sulfate salt and naltrexone as the HCl salt were prepared for subcutaneous injection in 0.9% NaCl solution.

Apparatus
For the purposes of measuring fluid intake at intervals ranging from 0.5 to 48 h, we used an automated drinking apparatus (Imétronic, Pessac, France). This apparatus presented the animal, housed in a standard shoebox cage, two reservoirs. Fluid volumes consumed from each reservoir were accurate to 0.32 ml. After 0.32 ml was consumed from either reservoir, they were automatically refilled. Fluid delivery and data collection were managed by a PC, allowing the simultaneous study of 16 rats. The dimensions of the cage measured 33 x 21 x 18 cm (l x w x d).

Procedures
Study 1: short term exposure to ethanol Eight female (211–236 g) and seven male (303–389 g) HEP rats from the seventh generation were used in this study. All animals were 3 months old at the beginning of the study. The protocol was conducted in four parts, as follows.

Part 1: habituation to the drinking apparatus. All animals were placed in cages in the automated drinking apparatus for 20 days prior to exposure to alcohol. Water was available from both reservoirs ad libitum as was food.

Part 2: baseline water consumption and initiation of two-choice ethanol (10%v/v) versus water. Baseline water consumption was measured over 8 days and was followed by 14 days of two-choice ethanol versus water. All data were collected in 2-day blocks. As was done in all two-choice procedures throughout the series of studies, the position of the fluids was alternated every 48 h.

Part 3: two-choice water versus 5, 10, 20 or 40% ethanol (v/v). On the day following the two-choice, 10% (v/v) study, the animals were tested for consumption of different ethanol concentrations. This part of the study was conducted to determine the effect of changing ethanol concentrations on the tendency of the animals to ‘titrate’ their ethanol dose. Each animal was given 48 h exposure to each of the concentrations in the automated distributor, in a Latin square design.

Part 4: the effect of repeated deprivation periods on ethanol consumption. Following the differential concentration protocol, the animals were given a choice between 10% ethanol and water as in part 2 for 4 days. At the end of this period, the animals were given water as their sole source of fluid for five days with alcohol replaced (vs. water) afterwards for 48 h. This sequence was repeated three times. Alcohol and water volumes consumed were measured in 0.5-h segments beginning immediately after replacement.

Study 2: long-term exposure to ethanol followed by repeated deprivation Seven females (254–290 g) and five males (380–430 g) from the eighth generation were used in this study. The animals were 5 months old at the beginning of the study and were housed individually under the same conditions as described above. The study was organized into three parts and the animals were tested in that order.

Part 1: long-term, two-choice (EtOH, 10%v/v vs. water) testing in the home cage. The animals were given a choice between 10% ethanol and water for a total of 20 weeks. Because of the logistics of maintaining the automatic drinking machine, the animals were housed in the normal shoebox cages and two bottles were presented continuously for 16 weeks, with the positions of water and ethanol alternated twice weekly, when the amounts consumed from the bottles and body weights were measured.

Part 2: two-choice (EtOH, 10%v/v vs. water) testing in the machine. At the end of part 1, the animals were introduced into the automatic drinking machine and maintained there for 4 weeks. Consumption values were now recorded at 48-h intervals. As shown below, there was a dramatic decrease in ethanol consumption among all animals when they were introduced to the machine. To control for the novelty effect the data from the last 16 days were considered to represent true baseline values.

Part 3: effects of alcohol deprivation and experimental manipulations to either enhance or diminish the abstinence effect. All protocols consisted of ethanol deprivation for 5 days followed by 48 h of reinstatement of two-choice ethanol (10% v/v) versus water. This series was conducted over 6 weeks, as follows. (a) Baseline deprivation for 5 days followed by 48 h of reinstatement. Week 1. (b) Pharmacological intervention during reinstatement. Animals were injected s.c. with saline (1 ml/kg), morphine (2 mg/kg) and naltrexone (1 mg/kg) 0.5 h prior to reintroduction to alcohol. All injections were isovolumetric. This protocol was conducted over 3 consecutive weeks with the order of treatments randomized for each rat. Weeks 2–4. (c) Adulteration of ethanol with quinine (0.1%). Week 5. (d) Addition of saccharine to the water (7.5 mmol/l). Week 6.

Data analysis
Ethanol consumption was converted to g/kg/day and ethanol preference was expressed as volume of ethanol divided by total fluid volume x100. Analysis of variance for a one between-subjects variable and a one within-subjects variable was used to evaluate differences between the sexes and repeated measures, respectively.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study 1: Short term exposure to ethanol
Fluid consumption The top panels of Fig. 1 illustrate the pattern of total fluid consumption across the 18 days of testing. The left panel depicts consumption over 24 h and the right panel shows the per cent consumption during the light phase of the daily cycle. For both measures, there was a significant effect of sex (F1,13 = 13.15, 36.92, respectively; P < 0.01). Also significant were the effect of blocks (F8,104 = 2.60, 3.32; P < 0.05, respectively). There were also significant interactions between sex and blocks (F8,104 = 3.93, P < 0.01 and 2.15, P < 0.05, respectively). The data reveal that, from the beginning, females drank more fluid than did the males and moreover drank more than males during the light phase of the quotidian cycle. Both total and diurnal fluid drinking increased when alcohol was introduced as a free choice with tap water, but only in females.



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Fig. 1 Total fluid drinking (upper panels) and alcohol intake (lower panels) when water was available as the sole source of fluid (hatched area) or as a free choice versus ethanol (10% v/v). Left panels, intake expressed by reference to body weight; right panels, proportion of fluid (or alcohol) ingested during the light phase of the day.

 
Ethanol consumption The lower panels of Fig. 1 present the pattern of alcohol consumption over the 14 days of two-choice (10% v/v vs. water) testing. As with total fluid consumption, females drank significantly more ethanol than did the males throughout the experiment (left panel) and a greater proportion of their ethanol ration during the light phase (right panel) of their 24-h cycle (F1,13 = 8.57, 6.11, respectively; P < 0.05). The tendency for females to increase their alcohol consumption across the 14 days of testing contributed to an overall main effect of blocks (F6,78 = 5.23, P < 0.01). The males, however, showed a consistent drinking pattern and thus contributed to the significant sex by blocks interaction (F6,78 = 2.45, P < 0.05). For diurnal consumption, there was neither main effect for days nor sex by days interaction (F < 1.0 for both). For the females, but not the males, diurnal ethanol consumption was a highly significant predictor of total ethanol consumption over 24 h (rdf7 = 0.87; P < 0.01).

Consumption of 5, 10, 20 and 40% v/v ethanol Analysis of variance of volumes consumed showed a significant sex effect (F1,13 = 17.08; P < 0.01), and a significant effect of concentration (F3,39 = 16.69; P < 0.01). Figure 2 presents the results and as can be seen, at every concentration, females consumed significantly more ethanol than did males (P < 0.05). Moreover both sexes increased their consumption between 5 and 20%, levelling off at 40% (except for a decline in the females between 20 and 40%).



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Fig. 2 Influence of the concentration of ethanol solution presented as a free choice with water, on ethanol intake, expressed as the amount of pure ethanol ingested per day and per unit of body weight.

 
Repeated ethanol deprivation Figure 3 presents mean volumes of ethanol and water consumed by male and female rats each 0.5 h for the last day prior to deprivation and the first day after ethanol reinstatement for the first replication. For the first 0.5 h following reinstatement, both females and males evinced a burst of increased ethanol drinking (F3,39 = 17.25; P < 0.0001). The means of the three replications were 6.94 and 3.99 ml/kg/30 min for females and males, respectively (or 0.547 and 0.315 g/kg of pure alcohol ingested in 30 min). However, after alcohol reinstatement there were no significant differences in ethanol consumption over the first day between the pre- and post-deprivation periods (F3,39 < 1.0), and alcohol consumption did not differ between the two successive days (F1,13 = 1.43). The three replications produced virtually identical results, thus showing no long-term effect of ethanol deprivation, nor any effect of repeated periods of deprivation.



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Fig. 3 Alcohol deprivation effect. Mean volumes of ethanol and water consumed by males (upper panel) and females (lower panel) each 0.5 h during the last day prior to the 5-day alcohol deprivation period and the first day after ethanol reinstatement. The hatched area indicates the night period.

 
Study 2: long-term exposure to ethanol followed by repeated deprivation
At the beginning of the study, we observed the same difference in consumption between sexes as we did for the short-term study [i.e. females drank considerably more than did the males (F1,10 = 13.72; P < 0.05)]; however, at the end of the 16 weeks there was no difference between the sexes. Figure 4 shows that the females decreased and males increased their ethanol consumption across the study. What is also shown in Fig. 4 is the sharp decrease in alcohol consumption, from 7 to 4.5 g/kg/day (F1,10 = 8.82; P < 0.05) when the animals were placed in the automatic distributor. During the last 16 days, when consumption was stabilized in the automatic distributor, the females showed superior consumption of the total amount of liquid (115 ml/kg/day) compared to males (87 ml/kg/day; F1,10 = 6.09; P < 0.05, data not shown); however, there was no difference between sexes in ethanol consumption (5.83 and 6.73 g/kg/day in males and females, respectively, F1,10 = 1.16, data not shown), so that preference for alcohol versus water was higher in males (92.5%) than in females (76.9%, F110 = 5.05, P < 0.05, data not shown). Moreover, at the end of the chronic ethanol exposure, there was no difference in diurnal ethanol consumption between sexes as had been observed in the short-term ethanol study (37.4% and 38.3% in males and females, respectively, F1,10 < 1.0).



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Fig. 4 Changes in alcohol intake and preference over several months of continuous access to a 10% ethanol solution versus water (two-bottle choice).

 
Deprivation following long-term ethanol consumption As was observed in the short-term ethanol study (data not shown), 5-day deprivation produced an initial increase in ethanol consumption in both males and females, observed during the first 0.5 h following reinstatement of ethanol (F1,10 = 79.71; P < 0.01). There was also a significant interaction between sex and deprivation. Females showed a larger initial increase than did males (F1,10 = 8.48; P < 0.05). After the first 0.5 h following alcohol reinstatement and on subsequent days thereafter, there appeared to be no difference in ethanol consumption pattern after reinstatement compared to the period before deprivation for either sex. A second deprivation/reinstatement cycle produced nearly identical results.

Effect of morphine and naltrexone on ethanol consumption following deprivation Figure 5 illustrates the effect of morphine and naltrexone on ethanol consumption following 5 days of deprivation. Pretreatment with morphine produced a significant augmentation (compared to control treatment) of ethanol consumption during the first 0.5 h following ethanol reinstatement (F1,10 = 9.41; P < 0.05), whereas naltrexone pretreatment had the opposite effect of diminishing the initial increase in initial consumption (F1,10 = 33.96; P < 0.01). Thereafter, there were no significant effects of either drug on ethanol consumption. Males and females were nearly identically affected by both drug pretreatments. With the exception of one naltrexone-treated rat, none of the animals drank water during the first half hour following ethanol reinstatement.



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Fig. 5 Effect of morphine and naltrexone on the alcohol deprivation effect.

 
Adulteration of ethanol with quinine following deprivation Adding quinine to ethanol after 5 days of deprivation (Fig. 6) produced an initial decrease in alcohol consumption for both males and females (F1,10 = 28.64; P < 0.01) and a decrease in 24-h ethanol consumption for the next 2 days (F1,10 = 22.41; P < 0.01).



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Fig. 6 Influence of adulteration of the alcoholic solution by quinine or of adding saccharine to water on daily alcohol drinking after 5-day alcohol deprivation (D1 and D2 are respectively the first and second day after alcohol reinstatement).

 
Effect of addition of saccharine to water following ethanol deprivation Addition of saccharine to the water following 5-day ethanol deprivation had no effect on ethanol consumption in either males or females during the first 0.5 h following ethanol reinstatement (overall mean, control (10% ethanol vs. water) 8.24 ± 1.04 ml/kg/0.5 h, 10% ethanol vs. saccharine 9.55 ± 0.97 ml/kg/0.5 h). However, on the two days following alcohol reinstatement, ethanol consumption was reduced 70–90%, compared to pre-deprivation (Fig. 6). Males and females were equally affected and redirected their drinking preference to saccharine predominantly.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this series of studies, we have confirmed the observations of others (Myers et al., 1998Go; Terenina-Rigaldie et al., 2003bGo) that the HEP rats consume large quantities of ethanol when given a choice and that females consume significantly more ethanol than do males from this line. This work, however, extends these observations to show that the sex difference is nearly completely attributable to the fact that females drink more alcohol during the light period of the 24-h cycle than do males. Moreover the sex-related difference in ethanol completely disappears after several weeks of two-choice ethanol testing and is attributable to the increase in diurnal ethanol consumption by males. We also observed a gradual increase in ethanol consumption by males. Together, these findings are consistent with our previous observation (Terenina-Rigaldie et al., 2003aGo,bGo) that there may be qualitative in addition to quantitative differences between male and female HEP in ethanol consumption.

The most important finding of this work, however, is the failure to produce a robust ADE following weeks and months of two-choice preference testing in which both males and females consumed large quantities of ethanol on a daily basis. Certainly, the animals increased their intake and obtained pharmacologically significant amounts of alcohol during the initial 30-min period and morphine and naltrexone treatments moved this initial consumption in directions consistent with ADE. The best evidence against development of dependence, however, is the almost total cessation of alcohol consumption (except during the first 0.5 h of alcohol reinstatement) when saccharine was added to water in the second bottle. One might expect that if the animals were made dependent on ethanol they would show increased consumption for an extended period following deprivation, irrespective of taste factors. Adding quinine (0.1% is barely perceptible to humans) to the ethanol following a period of deprivation decreased ethanol consumption for 2 days following reinstatement and adding saccharine to water nearly completely distracted the animals' attention away from the ethanol. Thus, it is obvious that if the HEP rats develop ADE, this effect is ephemeral and that the HEP rats are more sensitive to external sensory cues than to whatever internal effects that alcohol and its abstinence may produce.

As reviewed by Herz (1997)Go, opioid receptor agonists and antagonists change both alcohol drinking and the intake of other taste reinforcers such as saccharine (Moufid-Bellancourt et al., 1996Go). Indeed, we applied these drug treatments to determine whether we could differentiate between the types of reinforced ingestion, especially considering that naltrexone is used to treat alcoholism (O'Malley et al., 2003Go). In fact, morphine increased and naltrexone decreased the ingestion of all of these substances. Thus, we observed the same effects and in the same timeframe as alcohol drinking following abstinence alone as would be predicted by the extant literature. Furthermore, as reviewed by Kampov-Polevoy et al. (1999)Go, alcohol and saccharine reinforcing properties are linked, and that could be through a common genetic mechanism (Terenina-Rigaldie et al., 2003aGo,bGo). All these data strongly support the hypothesis that taste is important in the reinforcing properties of alcohol in the HEP rats.

Now, how do these results fit with Cicero's criteria? For criterion 1, all of the ethanol was ingested orally. As to whether the animals ingested sufficient ethanol to be pharmacologically significant, we rely upon the earlier work of Myers et al. (1998)Go who showed that the volumes of ethanol consumed were similar to ours and produce blood ethanol contents that are pharmacologically significant. As for whether the animals drink ethanol for its post-ingestive effects, we believe that three findings argue against this in the HEP rat. First is the observation that after 4 months of daily consumption of substantial quantities of ethanol, when the animals' environment was changed (i.e. to the automatic distributor), their ethanol consumption dropped nearly 50%. Second, when the ethanol was adulterated with quinine, the amount of ethanol consumed decreased significantly. Third and possibly most importantly, when saccharine was added to the water (the alternate choice), the animals' ethanol consumption dropped dramatically, their attention nearly totally focused on the saccharine. As to whether ethanol is reinforcing to the animals, we believe that to some extent it is. The high preference for ethanol solutions over water, the enhancement of the short burst of post-deprivation drinking by morphine and alternatively the decrease produced by naltrexone give some indirect evidence. Of course, this hypothesis would be better tested using an alcohol-contingent task. We did not measure dispositional tolerance to ethanol in these animals, however the functional tolerance appeared to increase in the males and decrease in the females as shown by changes in intake across 4 months. Finally, we observed no signs of physical dependence, nor an ADE effect.

So, now the question becomes, what aspect of alcoholism do the HEP rats simulate? Our results would seem to rule out an alcohol-dependent type, yet the animals consume quite large quantities of ethanol, more than nonselected stocks and as much as stocks that had been selected for high ethanol consumption. The seminal work of Cloninger (1987)Go and others (Babor et al., 1992Go) tell us that human alcoholism is in fact a collection of two or more syndromes related either primarily or secondarily to ethanol. For example the type of alcoholism characterized by dependence (Cloninger's type I) may show co-morbidity with depression and triggered by a stressful environment. Another type is seen in individuals who appear to be sensation-seeking, show various forms of antisocial or irresponsible behaviour consume large amounts of ethanol and apparently do not become dependent. For these individuals, it seems that ethanol is not a primary consideration, but an agent sought after because of its sensory properties, including rewarding effects. It may be in fact that in these individuals, ethanol intensifies sensory experiences. The HEP rats appear to have some traits in common with this latter type, especially as concerns their sensory reactivity. Is it, then that we have an animal model of alcohol misuse?


    ACKNOWLEDGEMENTS
 
Financial support was provided by L'Institut de Recherches Scientifiques sur les Boissons (IREB) and by L'Institut National de la Santé et la Recherche Médicale (INSERM) by way of Poste Orange Award to B.C.J. The authors thank Dr Robert D. Myers (East Carolina University, Greenville, NC) for supplying rat breeders and Yannick Mellerin for expert technical assistance.


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 DISCUSSION
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