The Author 2007. Published by Oxford University Press on behalf of the Medical Council on Alcohol.
Nicotine increases ethanol preference but decreases locomotor activity during the initial stages of chronic ethanol withdrawal
Laboratoire de Biologie du Comportement, Université catholique de Louvain, 1 Place Croix du Sud, 1348 Louvain-la-Neuve, Belgium
* Author to whom correspondence should be addressed at: Biologie du Comportement, Université catholique de Louvain, 1 Place Croix du Sud, 1348 Louvain-la-Neuve, Belgium. Tel: +32 10 474384; Fax: +32 10 474094; E-mail: dewitte{at}bani.ucl.ac.be
Received 10 October 2006; in revised form 17 December 2006; in revised form 11 January 2007; accepted 29 January 2007
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ABSTRACT |
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Aim: The ability of nicotine to modify withdrawal symptoms in rats chronically treated with alcohol, with respect to locomotor activity and ethanol or nicotine preference, has been evaluated in these studies. Methods and Results: Preliminary studies showed that locomotor activity increased 8–9 h after withdrawal from chronic nicotine intoxication, which was dose specific; it occurred in rats administered 0.15 mg/kg or 0.6 mg/kg but not the 0.3 mg/kg nicotine dose. Administration of nicotine, either acutely (0.3 mg/kg) during ethanol withdrawal, or chronically (0.15, 0.3 or 0.6 mg/kg) during the chronic alcohol treatment procedure, diminished locomotor activity, which increases significantly, approximately 6–7 h after withdrawal, in rats chronically treated with alcohol. Rats which were chronically treated with alcohol alone or in combination with nicotine, 0.3 mg/kg, showed an increase in ethanol intake when the free choice was performed between ethanol 10% and tap water; on the contrary, when the free choice was performed between ethanol 10% versus nicotine, 0.3 mg/kg, results showed a decrease in ethanol preference and a concomitant increase in nicotine preference. Conclusion: These studies clearly identified the modulatory effects of nicotine, at specific doses, on both motility and preference in rat chronically co-administered nicotine and ethanol.
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Introduction |
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TOPABSTRACTIntroductionMaterial And MethodsResultsDiscussionReferences |
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There is a high rate of co-occurrence between smoking and alcohol (Dawson, 2000
; Little, 2001; de Fiebre and de Fiebre, 2003); in fact between 70–90% of alcoholic subjects also smoke (Batel et al., 1995; Sher et al., 1996). Furthermore, alcoholics who smoke use more cigarettes per day than non-alcoholic smokers (Dawson, 2000) while ethanol consumption has been shown experimentally to increase cigarette smoking (Mintz et al., 1985). Such a close association between these two compounds might indicate that the action of one counteracts, at least in part, the action of the other, while another possibility is that the action of one may enhance the rewarding actions of the other (Alcohol Alert, 1998; Collins et al., 1998; Tizabi et al., 2002).
Individually these two drugs show some opposing effects. For example, nicotine enhances cognitive functions, e.g. behavioural arousal or alerting (Levin, 1992, while ethanol may disrupt these functions under certain conditions (Rezvani and Levin, 2003). Alcohol-induced attentional impairments may be reversed by nicotine, (which, by itself, improves attention), while, on the other hand, alcohol may block such improvements induced by nicotine. For example, alcohol blocked the nicotine-induced attentional improvement when the two drugs were co-administered (Rezvani and Levin, 2003) although nicotine diminished some aversive effects of ethanol (Hetzler and Martin, 2006).
Nicotine may counteract ethanol-induced damage in specific brain regions. When rats were administered ethanol intragastrically, (to mimick 4 days binge drinking), followed by intradermally administered nicotine, ethanol-induced damage in the olfactory bulb was reduced but not in the cortical or hippocampal regions (Penland et al., 2001). In contrast, in vivo proton magnetic resonance spectroscopic imaging of chronic alcoholic subjects during 1 week of abstinent, (14 smokers and 10 non-smokers) showed exacerbated alcohol induced neuronal injury and cell membrane damage in the frontal lobes of chronic cigarette smokers (Durazzo et al., 2004).
Nicotine may play a role influencing alcohol consumption; cessation from smoking may increase (Carmelli et al., 1993) or decrease (Kohn et al., 2003; Friend and Pagano, 2005) its consumption. Its influence in modifying withdrawal symptoms during alcohol detoxification remains unclear. Some reports have suggested that nicotine intake (cigarette smoking) might diminish withdrawal symptoms in human although there have been no controlled clinical trials. In animal models of ethanol intoxication, nicotine attenuated the increase in glucose utilization in the mouse cerebellum (Anwer and Dar, 1995) the motor incoordination (Dar et al., 1994) as well as reducing the effects of ethanol on both reference and working memory in rats (Tracy et al., 1999). However, rats withdrawn from chronic alcohol treatment exhibited greater sensitivity toward tremorigenic effects of nicotine compared to controls (Gothoni, 1983; Gothoni and Ikola, 1985). Therefore there are many examples where interactions occur between nicotine and ethanol, although considerable variations between these studies exist. In part, this is due to the different models of ethanol intoxication used, e.g. acute or chronic alcohol, as well as the mode of drug administration.
In our recent microdialysis studies, (Lallemand et al., 2006) we have identified significant decreases in nucleus accumbens glutamate microdialysate release during the first 24 h of ethanol withdrawal after nicotine administration, either acutely during the withdrawal period or chronically with the ethanol intoxication regime. Therefore in the present studies, the behavioural responses of rats, which had received a comparable regime, have been investigated further, with respect to locomotor activity and preference for ethanol and nicotine during ethanol withdrawal. Such results will help to elucidate the role played by glutamate in mediating behavioural changes in the rats chronically treated with alcohol receiving concomitant daily p.o. nicotine administration.
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Material And Methods |
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Male Wistar rats were individually housed in standard plastic cages and maintained at a constant temperature (22° C) in a light controlled environment (12 light/12 dark light cycles, light on 8 am). They were given free access to commercial rat chow and either tap water or nicotine solution depending on the experimental study. All animal procedures were in strict accordance with the recommendations of EEC (86/609/CEF) and with the Belgian ‘projet de loi’ (Moniteur Belge 19.02.1992, p. 3437) on the care and use of laboratory animals.
Nicotine solution preparation
Nicotine tartrate (Sigma, St. Louis, MO, USA) was dissolved in isotonic saline, (60 mg/100 ml) and solutions were prepared at concentrations of 0.0018 mg/ml (0.15 mg/kg), 0.0036 mg/ml (0.3 mg/kg) and 0.0072 mg/ml (0.6 mg/kg) in water. The concentration of each solution was adjusted every day, according to the rat's liquid consumption and body weight, to ensure that each rat received a concentration of nicotine equivalent to 0.15, 0.3 or 0.6 mg/kg/day. Figure 1 shows the different experiments as a flowchart diagram.
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In preliminary studies, nicotine was administered to naïve rats to ascertain appropriate doses for the chronic alcohol studies.
Experiment 1
Rats (250–300 g) had access to one drinking bottle that contained 0.0018 mg/ml (0.15 mg/kg), 0.0036 mg/ml (0.3 mg/kg) or 0.0072 mg/ml of nicotine (0.6 mg/kg) (see Fig. 1). The consumption was recorded daily and adjusted accordingly to give the required dose. After 55 days the locomotor activity was recorded during the initial 18 h of nicotine withdrawal by the MacLab system which has been described by Meert et al. (1992). Briefly, the apparatus consisted of plexiglas test cages (25 x 24 x 25 cm). The floor consisted of a plexiglas plate (45 x 23 x 0.6 cm) mounted at each corner such that it bent freely. Underneath the middle of this plate, two pieces of piezo film (200 x 100 x 0.025 mm, polymeric PVF2) were glued and connected with an amplifier, such that deformations of the cage floor resulted in a piezoelectric response of each of the piezo films. One differential amplifier first summed these electric signals and the output of the signal was then filtered by a bandpass filter between 6 and 12 Hz (18 dB/oct slope). This end signal was sent to an eight-channel MacLab connected to a Macintosh Performa 630. A chart file enabled quantification of the frequencies of the pulse (Dahchour and De Witte, 1999). Locomotor activity of each rat was recorded for each 60 min interval during the withdrawal period of 18 h. Any movements made by the rat, i.e. mobile activity (moving from one area to another), static activity (tremor or grooming) or rearing, was recorded by this analytical system.
Experiment 2 Rats (300–350 g) had access to two drinking bottles, one containing tap water and the other a nicotine solution of 0.0018 mg/ml (0.15 mg/kg), 0.0036 mg/ml (0.3 mg/kg) or 0.0072 mg/ml of nicotine (0.6 mg/kg) (see Fig. 1). The consumption was recorded daily. The position of the drinking bottles was changed daily to avoid position preference.
Chronic alcohol treatment
The animals (300–400 g) were individually housed in a plastic chamber (120 x 60 x 60 cm) and chronically intoxicated by inhalation of ethanol vapour for 4 weeks. Ethanol concentration was increased from 15 to 24 mg/l in air, in successive steps of 1 mg/l every 2–3 days, so that the average blood ethanol concentration continued to rise (Le Bourhis, 1975; Aufrère et al., 1997). Blood was collected from the caudal portion of each rat's tail once per week during the chronic alcohol treatment period and twice per week at the end of the treatment period. The concentration of ethanol in the blood samples was assayed by the alcohol-dehydrogenase-based method (Boehringer-Mannheim, Germany).
Experiment 3: Acute i.p. nicotine injection at 6 h after commencement of ethanol withdrawal (see Fig. 1)
On removal from the alcohol chamber, the rats were placed in the MacLab system cages to monitor locomotor activity (Lallemand and De Witte, 2006). Recordings then commenced. After 6 h the rats received an acute i.p. injection of nicotine, 0.3 mg/kg, or saline. The withdrawal locomotor activity was recorded for a further 12 h.
Chronic nicotine administration during chronic alcohol treatment
During chronic alcohol treatment, the drinking bottles contained a nicotine solution, 0.0036 mg/ml or tap water for control animals. The volume of nicotine solution was adjusted every 2–3 days, according to the liquid consumption and the weight of the rat, so that each rat received 0.3 mg/kg.
Experiment 4: Free choice between ethanol 10% v/v versus water in rats chronically treated with alcohol +/– nicotine, 0.3 mg/kg (see Fig. 1) At the end of chronic alcohol treatment, the animals underwent three successive steps:
Firstly, a full beverage deprivation i.e. the water or nicotine bottle was removed during the last 6 h of the chronic ethanol administration procedure and the following 18 h of the withdrawal period. Locomotor activity was recorded during this time. This 24 h period of no access to drinking solution is needed to increase the motivation of the rats to drink in the next step.
Secondly, the rats were presented with a 10% v/v ethanol solution as the sole drinking fluid during the following 24 h. During this time, the mean ethanol consumption was recorded.
Thirdly, after the 24 h period the rat had a choice of liquid intake between water and an ethanol solution, 10% v/v (Le Bourhis, 1975). This experiment lasted for 30 days. This experimental period is called free-choice paradigm. During this time, the fluid intake was recorded daily and expressed as a percentage of total fluid intakes or as alcohol intake (g/kg body weight). The position of the drinking bottles was changed randomly every day to avoid position preference.
Experiment 5: Free choice between nicotine 0.3 mg/kg versus water in rats chronically treated with alcohol +/– nicotine, 0.3 mg/kg (see Fig. 1) In this experiment, the protocol is identical to experiment 4, except that the ethanol solution was replaced by a nicotine solution, 0.0036 mg/ml corresponding to 0.3 mg nicotine/kg/day.
Experiment 6: Free choice between nicotine 0.3 mg/kg versus ethanol 10% v/v, in rats chronically treated with alcohol +/– nicotine, 0.3 mg/kg (see Fig. 1) In this experiment, the protocol is identical to experiment 4, except that tap water was replaced by a nicotine solution, 0.0036 mg/ml corresponding to 0.3 mg nicotine/kg/day.
Experiment 7: Withdrawal locomotor activity after chronic alcohol treatment +/– nicotine (0.15, 0.3 and 0.6 mg/kg/d) (see Fig. 1) In this experiment the rats were co-administered ethanol by the vapourization method and nicotine orally at concentration of either 0.15, 0.3 and 0.6 mg/kg and then locomotor activity ascertained during the initial period of withdrawal.
Statistical evaluation The results are presented as mean ± standard error of the mean (S.E.M.). Data were analyzed by one-way analysis of variance (ANOVA) with repeated measures or two-way ANOVA with repeated measures on time for each treatment group versus control to assess the significance. Where appropriate, post hoc pair wise comparisons were analyzed by Fisher protected least significant difference test (GB-Stat 5.3 for Windows, Dynamic Microsystems, MD, USA). Criterion for significance was set at P < 0.05 for all tests. A t-test was used to assess the effect of nicotine treatment on the first day ethanol consumption with forced ethanol drinking. The criterion of significance was set at P < 0.05.
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Results |
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Experiment 1: Nicotine solution alone as sole liquid source
Naïve rats were offered one of the nicotine solution equivalents to 0.15, 0.3 or 0.6 mg/kg for 55 days, as the sole liquid source. At the lowest dose, 0.15 mg/kg, the rats consumed a constant nicotine volume of approximately 30 ml (Fig. 2(a)). A transient increase in nicotine intake was evident after 40 days for the 0.3 mg/kg dose. For the highest dose, 0.6 mg/kg the intake was reduced only during the first 5 days after which the consumption remained constant for the remaining 55 days. The nicotine amount ingested by the rats was equivalent to the dose given (Fig. 2(b)). The total volume of nicotine solutions drank is summarized in Table 1(a), as well as animal weights at commencement and completion of the study. The motility of these rats was assessed during the first 18 h of withdrawal from each dose. In the rats which had received either the 0.15 or 0.6 mg/kg nicotine dose, significant increases in motility, commencing at 8 h and 9 h respectively, were noted (main effect: F(3, 46) = 13.6139; P < 0.0001) and continued for the period of the experiment (Fig. 3(a)). In contrast, the rats that had received a chronic nicotine dose of 0.3 mg/kg for 55 days, showed no significant increase in motility between 8–9 h during this withdrawal period (Fig. 3(b)), although the motility was marginally increased by comparison to the controls during this withdrawal period.
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Experiment 2: Free choice between water versus nicotine
It was noteworthy that when naïve rats had free choice between water or a nicotine solution (0.15, 0.3 or 0.6 mg/kg), the nicotine intake was approximately 50%, i.e. no preference was noted (Fig. 4(a)). However with the lowest dose, 0.15 mg/kg, the consumption of the nicotine solution was only 30% after 5 days in comparison to water intake, although intake did gradually increase during the experimental time period of 40 days. The rats ingested only 2/3rd of the expected dose (Fig. 4(b)). In contrary, when they have no choice, the ingested dose is equivalent to the dose administered (Fig. 2(b)). The volume of drinking solutions is summarized in Table 1(a).
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Experiment 3: Withdrawal locomotor activity after chronic alcohol treatment + acute nicotine i.p injection 0.3 mg/kg after 6 h of withdrawal
A dose of 0.3 mg/kg was used to study the effects of nicotine on alcohol withdrawal since this dose had been shown in the preliminary studies, (Experiment 1) to reduce locomotor activity between 8–9 h.
Administration of an acute nicotine injection, 0.3 mg/kg, 6 h after the start of ethanol withdrawal in rats chronically treated with alcohol, induced significant decreases in movements between 7–9 h, in comparison to the rats which had received only an acute saline injection, (interaction between treatment and time: F(17357) = 2.0822; P = 0.0073) (Fig. 5).
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Free choice between, (i) 10% ethanol versus water, (ii) nicotine, 0.3 mg/kg versus water and (iii) 10% ethanol versus nicotine, 0.3 mg/kg, in rats chronically treated with alcohol +/– nicotine, 0.3 mg/kg, for 30 days (Experiments 4–6)
The volume of drinking solutions is summarized in Table 1(b).
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Experiment 4: 10% ethanol versus water
Ethanol intake significantly increased from day 4 to day 9 in rats which had been chronically co-administered ethanol and nicotine in comparison to rats which were chronically treated alone with alcohol (ANOVA 1 between groups F(79) = 5.048; P < 0.0001) (Fig. 6(a)). The water consumption was not significantly different between the two groups (Fig. 6(b)).
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Experiment 5: Nicotine, 0.3 mg/kg versus water
The rats chronically treated with alcohol which had received nicotine or not during the chronic alcohol treatment procedure showed a preference for nicotine; the consumption of nicotine being approximately 70% of the total liquid consumption, (Fig. 7(a)), which was equivalent to a nicotine intake of approximately 0.3 mg/kg, (Fig. 7(b)).
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Experiment 6: 10% ethanol versus nicotine, 0.3 mg/kg
There was a significant transient decrease in ethanol preference from day 6 to day 9 in rats chronically co-administered ethanol and nicotine which was paralleled by a significantly increased nicotine preference (ANOVA 1 between groups F(53) = 1.8123; P = 0.0008) (Fig. 8). After these times no significant preference for either ethanol or nicotine was recorded for either group.
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Experiment 7: Blood ethanol content and withdrawal locomotor activity in rats after chronic alcohol treatment +/– chronic nicotine administration, (0.15, 0.3 or 0.6 mg/kg)
The blood ethanol concentration increased steadily in each group of rats to reach a final concentration ranging between 50–62.5 mM (Fig. 9). During this period, the increases in blood ethanol concentration were constant between day 10 and day 30 for all groups of rats. However the rats chronically treated with alcohol together with nicotine showed significantly higher blood ethanol concentrations than the group chronically treated with alcohol (main effect: F(3.69) = 2.773; P = 0.0479) (Fig. 9) between day 15 and 20 for 0.15 mg/kg, at day 25 for 0.3 mg/kg and at day 15 for 0.6 mg/kg. During the initial period of withdrawal after chronic ethanol administration +/– nicotine, (0.15, 0.3 or 0.6 mg/kg) a diminution in locomotor activity was evident for each group of rats which had received the nicotine dose, although this just failed to reach significance (main effect: F(3.94) = 0.7694; P = 0.0514), data not shown. The volume of drinking solutions is summarized in Table 1(c).
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Discussion |
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Since ethanol and nicotine are often co-abused and individually show comparable withdrawal symptoms, it was of interest to investigate whether withdrawal symptoms would be enhanced or diminished after co-administration of these two drugs. Specifically, in these present studies, we have evaluated whether nicotine, administered chronically or acutely, is able to modify locomotor activity in rats chronically treated with ethanol during the initial stages of withdrawal. In rats, that had a comparable drug regime, we have shown significant changes in glutamate release in microdialysis experiments (Lallemand et al., 2006
). It was also of interest to ascertain whether there is a preference for alcohol or nicotine in these rats.
Nicotine has known reinforcing affects on the brain, in part, attributable to the activation of specific nicotinic acetylcholine receptor subunits with the subsequent elevation of extracellular and synaptic dopamine concentrations. Nicotine blood levels in human would appear to reach a constant nadir, regardless of the cigarette nicotine content, which may be due to the presence of gene CYP286, where various mutations will either enhance or reduce nicotine metabolism (Pianezza et al., 1998). Rats which received a nicotine solution for 55 days, at doses of 0.15, 0.3 or 0.6 mg/kg, or a choice of nicotine or water, showed a constant intake of nicotine regardless of dose, although no nicotine preference.
The most prominent symptoms of nicotine withdrawal in rats include foot licks, scratches, yawns and shakes, the latter being used in these present studies. There was an increase in locomotor activity 8–9 h after withdrawal from chronic nicotine administration, which was dose specific; occurring in rats administered 0.15 and 0.6 mg/kg doses but not with the 0.3 mg/kg dose. The lowest chronic dose of nicotine evoked the severest symptoms with respect to locomotor activity, thereby not confirming other studies where the severity of nicotine withdrawal symptoms is proportional to the amount of prior nicotine exposure (Malin et al., 1992). Nicotine increases brain nicotinic acetylcholine receptors intensities (Yoshida et al., 1982) at specific nicotine concentrations, thereby modulating the release of several neurotransmitters by activating 
4β 2 nicotinic receptors (Aistrup et al., 1999; Cardosa et al., 1999). Interestingly, the amount of nicotine consumed in the form of tobacco does not appear to be an accurate predictor of withdrawal severity in human smokers (Hughes et al., 1991).
In our previous studies of withdrawal from chronic alcohol treatment by the vapourization method in rats, we identified an increase in locomotor activity 6–7 h after cessation of ethanol administration (Dahchour and De Witte, 1999). Nicotine administration clearly reduced this hyper-locomotor activity during the initial ethanol withdrawal period, up to 18 h, when given, either acutely, at a dose of 0.3 mg/kg, during the withdrawal period, or chronically, (at doses of 0.15. 0.3 or 0.6 mg/kg) during the chronic alcohol treatment period. In previous studies, such alterations in locomotor activity were related to glutamate release during the withdrawal period from chronic alcohol treatment (Dahchour and De Witte, 1999). However, our recent microdialysate studies (Lallemand et al., 2006) showed that glutamate release was significantly reduced only after the co-administration of nicotine at a dose of either 0.15 mg/kg or 0.3 mg/kg during the chronic alcohol treatment period during the first 12 h of withdrawal. Behavioural studies undertaken in these current studies showed decreases in locomotor activity with all three doses although this failed to reach significance (P = 0.054). In other studies, intracerebellar infusions of nicotine or pre-treatment with nicotine significantly attenuated ethanol-induced motor incoordination in a dose dependent manner (Dar et al., 1994) or ethanol induced impairment of both aerial righting reflex and performance (Tracy et al., 1999). In a recent study by Saellstroem Baum et al. (2006) an increase in glutamate release was reported after an acute nicotine injection to an ethanol intoxicated binge drinking model during the initial withdrawal period. This would relate possibly to the responses observed after an acute dose of nicotine as previously reported by our group (Kashkin and De Witte, 2004). Further studies are needed to clarify the role of glutamate in the changes in locomotor activity that occur during ethanol withdrawal since this present data indicates that other factors rather than glutamate alone are involved.
It has been suggested that administration of nicotine to rats chronically treated with alcohol might increase alcohol consumption. In the study by Lopez-Moreno et al. (2004) nicotine administration, at doses 0.2, 0.4, and 0.8 mg/kg, during the ethanol deprivation period increased alcohol consumption. Nicotine also increased voluntary drinking of alcohol by rodents in several experimental paradigms (Soderpalm et al., 2000) while specific doses, (0.25 and 0.5 mg/kg), increased operant responding of rats for ethanol (Clark et al., 2001). In our present studies, naïve rats preferred ethanol rather than ethanol + nicotine. After chronic co-administration of ethanol and nicotine, rats showed a transient increase in ethanol intake when the free choice was performed between ethanol 10% versus tap water. In contrast when the free choice was performed between ethanol 10% versus nicotine 3 mg/kg, these rats preferred nicotine to ethanol. However Rezvani and Levin, (2003) showed choice impairment when these two drugs were administered together which was not evident when the drugs were administered individually.
The previous studies that reported that co-administration of nicotine and ethanol, intragastrically, to neonatal (Chen et al., 1998, 2001) or adult female animals (Parnell et al., 2006) reduced circulating blood ethanol levels were not confirmed. Since the rats in these present studies were chronically treated with alcohol via the vapourization method, the nicotine-induced delay in gastric emptying, (Nowak et al., 1987; Scott et al., 1993) would not be implicated.
These studies clearly identified the modulatory effects of nicotine, at specific doses, on both motility and preference in rats chronically co-administered nicotine and ethanol. There were no correlations between locomotor activity and glutamate release during the initial withdrawal period while nicotine preference was noted in the animals which received nicotine 0.3 mg/kg. However, future studies may help to identify nicotine's effect on the withdrawal symptoms from ethanol such that better therapies may become available for detoxifying alcohol abusers.
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ACKNOWLEDGEMENTS |
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This work has been supported by the Fonds de la Recherche Scientifique Médicale (FNRS ref.3.4589.02 and FNRS ref. 3.4502.06) and the ERAB—European Research Advisory Board.
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