EFFECTS OF CB1 CANNABINOID RECEPTOR BLOCKADE ON ETHANOL PREFERENCE AFTER CHRONIC ALCOHOL ADMINISTRATION COMBINED WITH REPEATED RE-EXPOSURES AND WITHDRAWALS

FRÉDÉRIC LALLEMAND1, PHILIPPE SOUBRIÉ2 and PHILIPPE DE WITTE1,*

1 Laboratoire de Biologie du Comportement, Université Catholique de Louvain, Louvain-la-Neuve, Belgium and 2 Sanofi-Synthélabo Recherche, Montpellier, France

* Author to whom correspondence should be addressed at: Biologie du Comportement, Université Catholique de Louvain, 1 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 27 March 2004; first review notified 11 May 2004; in revised form 1 July 2004; accepted 3 July 2004)


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: The cannabinoid CB1 receptor antagonist, SR141716A, differentially affects the ethanol preference of chronically alcoholized rats when administered during cycles of ethanol exposure and withdrawal. In this study, ethanol preference was investigated in chronically alcoholized rats that underwent regular withdrawal periods during which the brain cannabinoid CB1 receptor antagonist, SR141716A, was administered. Methods: The cannabinoid receptor antagonist SR141716A, 3 or 10 mg/kg/day, was administered i.p. to Wistar rats at the conclusion of a 4-week period of chronic alcoholization, as they commenced a cycle of alcohol withdrawal for 10 days followed by a period of 10 days chronic ethanol exposure. In a second set of experiments, an additional cycle of ethanol withdrawal and re-exposure was given. Preference for ethanol versus water started at the end of the first or second chronic ethanol re-exposure for a period of at least 30 days. Results: In rats pretreated with the higher dose of SR141716A, ethanol preference during free choice was significantly increased after two ethanol re-exposures. In contrast, pretreatment with the lower SR141716A dose induced no significant change in ethanol intake during the free choice followed by either one or two ethanol re-exposures. Conclusions: SR141716A, 10 mg/kg/day dose, induced a significant increase in ethanol preference which was dependent on both the number of ethanol withdrawals and chronic ethanol re-exposures, while 3 mg/kg/day had no significant effect on ethanol preference.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
After chronic ethanol administration, at least two major amino acid neurotransmitter systems are compromised: the neuroinhibitory GABAergic function is down-regulated while glutamatergic function is up-regulated (Faingold et al., 1998Go). This leads to a complex cascade of neurochemical adaptive events in the central nervous system with the development of tolerance and dependence. Although the precise molecular mechanisms by which ethanol exerts its pharmacological effects in brain remain unknown, chronic exposure to ethanol is known to result in learning deficits (Shimizu et al., 1998Go), memory disruption (Fadda and Rossetti, 1998Go) as well as modification of several different neuronal signal transduction systems (Lovinger, 1989Go; Basavarajappa et al., 1997Go, 1998Go).

It has been reported that the cannabinoid system consists of two types of receptors, CB1 and CB2. CB1 receptors are widely expressed in the brain with specific neuronal locations (Herkenham et al., 1990Go; Lévénès et al., 1998Go; Navarro et al., 1998Go) while CB2 receptors are mainly localized in the peripheral nervous system and other tissues. The CB1 cannabinoid receptors are abundant in brain regions that play a role in the regulation of the reward circuits commonly activated by abused drugs including ethanol (Rodriguez de Fonseca and Navarro, 1998Go). The role played by the cannabinoid receptor during chronic ethanol intoxication has been investigated in many studies. Although anandamide levels are increased in the brain during chronic ethanol treatment, CB1 receptors are down-regulated. The CB1 receptor antagonist SR141716A inhibits ethanol intake, which may indicate a role for the endocannabinoid system in the pharmacology of ethanol actions (Basavarajappa and Hungund, 1999Go).

SR141716A binds with high affinity to central (CB1) but not to peripheral (CB2) cannabinoid receptor and acts as an antagonist of a variety of pharmacological and behavioural cannabinoid effects in rodents (Rinaldi-Carmona et al., 1994Go).

Chronic exposure to ethanol or cannabis will result in the same neuroadaptations in both mesencephalic dopaminergic cells projecting to the nucleus accumbens and amygdalar corticotrophin-releasing factor neurons (Rodriguez De Fonseca et al., 1999Go). The endogenous cannabinoid system is not only the neurobiological substrate of marijuana addiction, but is also a modulatory system for the main neurotransmitters involved in reward circuits, such as dopamine, opioid peptides, GABA and glutamate. Animal models have shown that drugs that are active at brain cannabinoid receptors are able to modulate ethanol, cannabinoid and opiate self-administration.

In recent studies SR141716A was shown to reduce alcohol-motivated behaviours in animal models of alcoholism (Arnone et al., 1997Go; Colombo et al., 1998Go; Gallate and McGregor, 1999Go; Freedland et al., 2001Go) which suggests that cannabinoid CB1 receptors are involved in the reinforcing properties of ethanol. In our previous study we demonstrated that the inhibitory action of SR141716A was dependent on the time of administration, that is during or after chronic alcoholization (Lallemand et al., 2001Go). It is well established that ethanol self-administration is maintained after chronic ethanol intoxication in both humans and animals for its reinforcing effects and prevention of adverse withdrawal effects (Rodriguez de Fonseca et al., 1999Go); therefore it is important to investigate the possible beneficial effects of CB1 cannabinoid receptor blockade on ethanol intake after repeated ethanol withdrawals and chronic ethanol re-exposures.

The results obtained from rat studies will have relevance to human studies on alcohol withdrawal as the rat and human CB1 cannabinoid receptors show high homology, with 93 and 97% identities at the nucleic acid and amino acid levels, respectively (Ameri, 1999Go).

In the present study we have investigated the effects of the CB1 receptor antagonist SR141716A, on ethanol preference, ethanol intake and total liquid consumption in rats which were exposed to repeated chronic ethanol re-exposures interrupted by repeated withdrawals, while receiving daily SR141716A treatment. More precisely, in a first set of experiments, the SR141716A treatment was administered to rats during a 10-day withdrawal period after a first chronic pulmonary ethanol administration that was followed by 10 days of chronic ethanol re-exposure (Fig. 1A). In a second set of experiments, the drug was administered during the 10-day withdrawal period following the first chronic pulmonary ethanol administration. This was followed by another 10-day period of chronic ethanol re-exposure followed again by a 10-day period of withdrawal. Finally there was another 10-day period of chronic ethanol re-exposure (Fig. 1B). These administrations should correspond more closely to those observed in alcoholic humans who have failed to maintain alcohol withdrawal while receiving pharmacological treatment. Nonetheless, major differences with humans remained: (1) the ethanol intoxication phase was forced rather than controlled by the animals, and (2) the effects on ethanol consumption were estimated in the absence of pharmacological treatment.



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Fig. 1. Schematic representation of the SR141716A treatment during the first (A) and the second (B) experimental procedure. Black bar represents SR141716A treatment period and shaded bar represents period in which rats were chronically treated with ethanol.

 

    SUBJECTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals were kept under standard conditions (normal 12 h light–dark cycles, constant room temperature 21°C) with food and water ad libitum during the entire experiments.

Chronic ethanol administration procedure
Male Wistar rats, average weight 340–400 g, were individually housed in plastic chambers (120 x 60 x 60 cm) and chronically intoxicated by inhalation of ethanol vapour over a period of 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 alcohol level (BAL) continued to rise (Le Bourhis, 1975Go; Aufrère et al., 1997Go). Blood was collected from the caudal portion of each rat's tail once per week during the alcoholization period and then twice per week at the end of the chronic ethanol treatment period, as well as at the end of each subsequent ethanol re-exposure. Blood samples were placed into a tube containing sodium fluoride. The concentration of ethanol in the blood samples was assayed by the alcohol dehydrogenase-based method (Boehringer-Mannheim, Germany).

SR141716A treatment
In a first set of experiment, SR141716A treatment [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride] started at the end of the first 4 weeks of chronic alcohol intoxication. Rats were injected i.p. with SR141716A at doses of 3 or 10 mg/kg/day at 15:00 hours over 10 days (corresponding to the first withdrawal period) and during the next 10 days of ethanol re-exposure. The animals were thus treated daily with SR141716A for a continuous period of 20 days. Each SR141716A dose has its own control group, which received only the vehicle under the same experimental conditions. A time schedule is shown in Fig. 1(A).

In a second set of experiments, SR141716A treatment protocol was the same as described above except that rats underwent one more 10-day withdrawal period followed by one more chronic ethanol intoxication while receiving SR141716A treatment. The animals were thus injected i.p. with SR141716A (3 or 10 mg/kg/day) for a continuous period of 40 days. The first and the second chronic ethanol re-exposure periods were achieved by using the same procedures as for the initial chronic ethanol treatment period. A time schedule is shown in Fig. 1(B).

Free-choice paradigm
In both experimental sets, the animals from each group underwent three successive steps at the end of the last chronic ethanol re-exposure, as follows. (1) A full beverage deprivation; that is the drinking bottles were removed during the last 6 h of the chronic ethanol administration procedure and the following 18 h withdrawal period. (2) Presentation of 10% (vol./vol.) ethanol solution as the sole drinking fluid during the following 24 h. During this time, the mean ethanol consumption was recorded (Table 1). (3) A free-choice beverage situation (water versus 10% [vol./vol.] ethanol solution) was presented for a minimum of 30 days.


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Table 1. (A) Blood alcohol level (BAL: g/l) at the end of the first ethanol intoxication and following ethanol re-exposure in first experimental set. (B) Blood alcohol level (BAL: g/l) at end of first ethanol intoxication and following the two ethanol re-exposures in second experimental set

 
During the free-choice period, the treatment with SR141716A was discontinued. The fluid intake was recorded daily (expressed as a percentage of total fluid intakes and as alcohol intake g/kg of body weight). The position of the drinking bottles was changed randomly every 2 or 3 days to avoid position preference.

Statistical analysis
The results are presented as mean ± standard error. Data were analysed by two-way ANOVA with repeated measures on time for each treatment group versus their control, to assess the significance of difference in blood alcohol level, ethanol intake and ethanol preference during the free-choice paradigm. Where appropriate, post-hoc pair-wise comparisons were analysed 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. Student's t-test was used to assess the significance between the treated and the control groups for the ethanol consumed during the 24 h preceding the beginning of the free choice paradigm periods in both experimental sets.

Products
SR141716A (Sanofi-Synthélabo Recherche, Montpellier, France) was suspended in 0.1% Tween 80 (Acros Organics, Belgium) in distilled water. Absolute ethanol used in the free-choice paradigm was obtained from Labotec (La Gleize, Belgium).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Results are presented as mean ± standard error. Blood alcohol levels (BAL) are summarized in Table 1. No significant differences in mean ethanol values were observed in any of the experiments, whether or not the drug was administered.

Ethanol consumption during the 24 h before the beginning of free choice, after the first ethanol re-exposure. (First experimental set)
The ethanol consumption during the 24 h that preceded the beginning of the free-choice paradigm of the animals, treated with either low or high doses of SR141716A, by comparison to their control showed no significant change (Table 2).


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Table 2. Ethanol consumed (ml and g/kg) during the 24 hours preceding the beginning of free choice

 
Free-choice paradigm in first experimental set
The water consumption as well as the ethanol consumption showed no statistical difference in rats that had been treated with either dose of SR141716A for 20 days before the beginning of the free choice paradigm.

More particularly, the ethanol intake (expressed in g ethanol/kg body weight) was not significantly altered for either dose (Fig. 2). The ethanol preference showed no significant changes after SR141716A pretreatment, 3 or 10 mg/kg/day, by comparison to their appropriate controls.



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Fig. 2. Time course of ethanol intake in g/kg body weight during the free choice of rats pretreated with SR141716A, 3 mg/kg/day (top) or 10 mg/kg/day (bottom), following the first experimental pattern. Open circles represent the ethanol intake in g/kg by control rats. Rats pretreated with SR141716A are represented by black triangles. Results are presented as means ± standard error.

 
Ethanol consumption during the 24 h before the beginning of free choice, after the second ethanol re-exposure. (Second experimental set)
The ethanol consumption during the 24 h before the beginning of free choice showed no statistical significance for the animals that were pretreated with 3 mg/kg dose. In contrast, the high dose of SR141716A induced a significant increase (t [17.796] = –2.418; P = 0.0357) in comparison to their controls (Table 2).

Free choice paradigm in second experimental set
During the free-choice period, the animals that were pretreated with SR141716A, 3 mg/kg/day, for 40 days before the free choice, showed no significant change in either water or ethanol consumption by comparison to their controls. There was also no significant change in the water consumption with the high dose of SR141716A.

In contrary, pretreatment with the high dose of SR141716A for 40 days before the free choice regime, induced a significant increase of ethanol consumption (F [1,528] = 4.808; P = 0.0435). The ethanol intake (expressed as g/kg body weight) during the free choice regime was not significantly different in SR141716A, 3 mg/kg/day, pretreated rats by comparison to the controls (Fig. 3, top). In contrast, pretreatment with 10 mg/kg/day SR141716A for 40 days induced a statistical significance for ethanol intake (F [1,496] = 7.7332; P = 0.0449) (Fig. 3, bottom).



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Fig. 3. Time course of ethanol intake in g/kg body weight during the free choice of rats pretreated with SR141716A, 3 mg/kg/day (top) or 10 mg/kg/day (bottom), following the second experimental pattern. Open circles represent the ethanol intake in g/kg by control rats. Rats pretreated with SR141716A are represented by black triangles. Significant time points between SR141716A and their own control are represented by *P < 0.05, **P < 0.01. Results are presented as means ± standard error.

 
The ethanol preference (expressed as percentage of ethanol consumed) during the free-choice regime for animals that were pretreated with SR141716A, 3 mg/kg/day, was not significantly different by comparison to the controls. In contrast, pretreatment with 10 mg/kg/day for 40 days before the free choice showed a significant interaction between pretreatment and time (F [33,495] = 1.519; P = 0.0344). This interaction was characterized by a significantly increased ethanol preference lasting for 27 days.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In a previous study, different SR141716A doses, i.e. 3 and 10 mg/kg/day, were known to induce a significant decrease of ethanol preference in naïve animals treated during 30 days with the cannabinoid receptor antagonist, while 1 mg/kg/day treatment induced no effect (Lallemand et al., 2001Go). In the current study, SR141716A, 3 or 10 mg/kg/day, was administered daily during 10 days of ethanol withdrawal followed by 10 days of chronic ethanol re-exposure (first experimental set); no difference was observed in total fluid consumption, in either ethanol intake or ethanol preference. When one more chronic ethanol re-exposure and one more withdrawal were implemented (second experimental set), the high dose of SR141716A induced a significant increase of ethanol preference lasting 27 days, as well as a significant increase in ethanol intake, while the low dose produced no significant effect.

These results were in contrast with those observed in previous experiments, when SR141716A administration decreased both ethanol self-administration (Rodriguez de Fonseca et al., 1999Go) and ethanol preference in sP rats (Colombo et al., 1998Go; Serra et al., 2001) or C57BL/6 mice (Arnone et al., 1997Go). In our previous studies we have shown that SR141716A acted differentially on ethanol preference, which was dependent on the time of administration, either during or after the chronic ethanol treatment, as well as the dosage (3 or 10 mg/kg/day) during withdrawal and free choice (Lallemand et al., 2001Go). When SR141716A (3 or 10 mg/kg/day) was administered during the chronic ethanol treatment, a significant increase in ethanol preference was recorded. In contrast, when SR141716A was given during both withdrawal and free choice, ethanol preference was significantly decreased.

In the present study, we administered SR141716A during the withdrawal stage and then subsequently during re-exposure to ethanol. After one withdrawal period followed by one ethanol re-exposure period, combined with daily administration of 3 or 10 mg/kg SR141716A, ethanol preference was not altered. In a previous study we showed that ethanol preference increased when SR141716A was administered during the chronic ethanol treatment and, in contrast, decreased when SR141716A was administered during the withdrawal (Lallemand et al., 2001Go). Consequently, in the current study, these two opposite effects could cancel each other, resulting in absence of an effect on ethanol preference.

In the second experimental set, this explanation could also be valid for the low dose of SR141716A but not for the high dose, as there was a significant increase of ethanol preference lasting 27 days, even though SR141716A was no longer administered. In this experimental set, the difference in comparison to the first experiment was the length of the SR141716A pretreatment—40 days versus 20 days. This longer period of administration could explain the increased duration of the ethanol preference with the high dose of SR141716A, but crucial data are lacking for this explanation as the half-life of SR141716A is not known. Another explanation could be the high dosage of SR141716A, i.e. 10 mg/kg/day; however, this dose was used in other studies by Colombo et al. (1998)Go, Lichtman et al. (2001)Go, Poncelet et al. (2003)Go as well as our previous study (Lallemand et al., 2001Go). In addition, SR141716A is known to have effects unrelated to CB1 receptors (Hungund et al., 2002Go). Moreover, Hajos and Freund (2002)Go showed non-CB1 cannabinoid receptors are present on glutamatergic terminals, which can be blocked by SR141716A at a concentration of 1 µmol/l in vitro. Nonetheless, in vivo studies have regularly used doses ranging from 0.1 to 10 mg/kg. We did not observe an effect due to the dose in the first experimental set with the high dose of SR141716A 10 mg/kg/day, but in the second experiment an effect was observed when the treatment period was increased 2-fold. In consequence, the duration of 10 mg/kg/day SR141716A treatment could explain the increase of ethanol intake.

In the second experimental set, the BAL at days 50 and 70 (i.e. at the end of each ethanol re-exposure) appeared to be lower with 10 mg/kg/day than with 3 mg/kg/day. Nonetheless, the levels at the end of the last ethanol re-exposure were similar to those assayed in the first experimental set for the same dose of SR141716A. Therefore, we can assume this difference is not involved in the increase of ethanol preference when the animals were pretreated with SR141716A 10 mg/kg/day during 40 days.

In conclusion, we observed that the administration of SR141716A, a CB1 cannabinoid receptor antagonist, induced an effect on ethanol preference when given in a time schedule comparable to that used by detoxifying alcoholics (Becker and Littleton, 1996Go). However, a 3 mg/kg/day dose of SR141716A had no effect on ethanol preference and ethanol intake, regardless of the number of ethanol re-exposures and ethanol withdrawal periods. In contrast the 10 mg/kg/day dose of SR141716A significantly increased ethanol preference.

The action of SR141716A would appear to be dependent on a variety of factors, which include the duration of the initial ethanol intoxication, the number of ethanol re-exposures and/or the number of ethanol abstinence periods; these two characteristics are difficult to separate. Nonetheless, as other studies of the lower dose of SR141716A, 3 mg/kg, also provoked beneficial effects by decreasing ethanol preference, the use of this dose in case of repeated ethanol re-exposure followed by ethanol abstinence would not have an adverse effect on ethanol preference. In consequence, the optimal use of SR141716A in order to maintain safe protracted alcohol withdrawal in the laboratory rat is to administer 10 mg/kg/day during the initial alcohol withdrawal period followed by a maintenance dose of 3 mg/kg/day, which would avoid the increase of ethanol preference when 10 mg/kg/day was given.


    ACKNOWLEDGEMENTS
 
This work was supported by grants (F.L.), the Fonds de la Recherche Scientifique et Médicale 3.4589.02 (P.D.), and the Institut de Recherches Economiques sur les Boissons 2002–2003 (P.D.). The authors thank Drs R. J. Ward and A. Dahchour and Ms A. D'Hauwer for technical assistance in the preparation of this article.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ameri, A. (1999) The effects of cannabinoids on the brain. Progress in Neurobiology 58, 315–348.[CrossRef][ISI][Medline]

Arnone, M., Maruani, J., Chaperon, F., Thiébot, M. H., Poncelet, M., Soubrié, P. and Le Fur, G. (1997) Selective inhibition of sucrose and ethanol intake by SR141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology 132, 104–106.[CrossRef][ISI][Medline]

Aufrère, G., Le Bourhis, B. and Beaugé, F. (1997) Ethanol intake after chronic intoxication by inhalation of ethanol vapour in rats: Behavioural dependence. Alcohol 14, 247–253.[CrossRef][ISI][Medline]

Basavarajappa, B. S., Saito, M., Cooper, T. B. and Hungund, B. L. (1997) Activation of arachidonic acid-specific phospholipase A2 in human neuroblastoma cells after chronic alcohol exposure: prevention by GM1 ganglioside. Alcoholism: Clinical and Experimental Research 21, 1199–1203.[CrossRef][ISI][Medline]

Basavarajappa, B. S., Cooper, T. B. and Hungund, B. L. (1998) Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain synaptic plasma membrane. Brain Research 793, 212–218.[CrossRef][ISI][Medline]

Basavarajappa, B. S. and Hungund, B. L. (1999) Chronic ethanol increases the cannabinoid receptor agonist anandamide and its precursor N-arachidonoylphosphatidyl-ethanolamine in SK-N-SH cells. Journal of Neurochemistry 72, 522–528.[CrossRef][ISI][Medline]

Becker, H. C. and Littleton, J. M. (1996) The alcohol withdrawal ‘kindling’ phenomenon: clinical and experimental findings. Alcoholism: Clinical and Experimental Research 20, 121A–124A.[Medline]

Colombo, G., Agabio, R., Fa, M., Guano, L., Lobina, C., Loche, A., Reali, R. and Gessa, G. L. (1998) Reduction of voluntary ethanol intake in ethanol preferring sP rats by the cannabinoid antagonist SR141716A. Alcohol and Alcoholism 33, 126–130.[Abstract]

Fadda, F. and Rossetti, Z. L. (1998) Chronic ethanol consumption: from neuroadaptation to neurodegeneration. Progress in Neurobiology 56, 385–431.[CrossRef][ISI][Medline]

Faingold, C. L., N'Gouemo, P. and Riaz, A. (1998) Ethanol and neurotransmitter interactions—From molecular to integrative effects. Progress in Neurobiology 55, 509–535.[CrossRef][ISI][Medline]

Freedland, C. S., Sharpe, A. L., Samson, H. H. and Porrino, L. J. (2001) Effects of SR141716A on ethanol and sucrose self-administration. Alcoholism: Clinical and Experimental Research 25, 277–282.[ISI][Medline]

Gallate, J. E. and McGregor, I. S. (1999) The motivation for beer in rats: effects of ritanserin, naloxone and SR141716A. Psychopharmacology 142, 302–308.[CrossRef][ISI][Medline]

Hajos, N., and Freund, T. F. (2002) Distinct Cannabinoid sensitive receptors regulate hippocampal excitation and inhibition. Chemistry and Physics of Lipids 121, 73–82.[CrossRef][ISI][Medline]

Herkenham, M., Lynn, A. B., Little, M. D., Johnson, M. R., Melvin, L. S., De Costa, B. R. and Rice, K. C. (1990) Cannabinoid receptor localization in brain. Proceedings of National Academy of Science USA 87, 1932–1936.

Hungund, B. L., Basavarajappa, B. S., Vadasz, C., Kunos, G., Rodriguez de Fonseca, F., Colombo, G., Serra, S., Parsons, L. and Koob, G. F. (2002) Ethanol, endocannabinoids, and the cannabinoidergic signaling system. Alcoholism: Clinical and Experimental Research 26, 565–574.[ISI][Medline]

Lallemand, F., Soubrié, P. and De Witte, P. (2001) The effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic ethanol administration. Alcoholism: Clinical and Experimental Research 25, 1317–1323.[CrossRef][ISI][Medline]

Le Bourhis, B. (1975) Alcoolisation du rat par voie pulmonaire. Comptes Rendus des Séances de la Société de Biologie et de ses filiales 169, 898–904.[ISI][Medline]

Lévénès, C., Daniel, H., Soubrié, P. and Crépel, F. (1998) Cannabinoids decrease excitatory transmission and impair long-term depression in rat cerebellar Purkinje cells. Journal of Physiology 510, 867–879.[Abstract/Free Full Text]

Lichtman, A. H., Poklis, J. L., Poklis, A., Wilson, D. M. and Martin, B. R. (2001) The pharmacological activity of inhalation exposure to marijuana smoke in mice. Drug and Alcohol Dependence 63, 107–116.[CrossRef][ISI][Medline]

Lovinger, D. M. (1989) Ethanol potentiation of 5-HT3 receptor-mediated ion current in NCB-20 neuroblastoma cells. Neuroscience Letters 122, 57–60.[CrossRef]

Navarro, M., Chowen, J., Carrera, M. R. A., del Arco, I., Villanúa, M. A., Martin, Y., Roberts, A. J., Koob, G. F. and Rodríguez de Fonseca, F. (1998) CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats. Neuroreport 9, 3397–3402.[ISI][Medline]

Poncelet, M., Maruani, J., Calassi, R. and Soubrié, P. (2003) Overeating, alcohol and sucrose consumption decrease in CB1 receptor deleted mice. Neuroscience Letters 343, 216–218.[CrossRef][ISI][Medline]

Rinaldi-Carmona, M., Barth, F., Héaulme, M. et al. (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Letters 350, 240–244.[CrossRef][ISI][Medline]

Rodriguez de Fonseca, F. and Navarro, M. (1998) Role of the limbic system in dependence on drugs. Annals of Medicine 30, 397–405.[ISI][Medline]

Rodriguez de Fonseca, F., Roberts, A., Bilbao, A., Koob, G. F. and Navarro, M. (1999) Cannabinoid receptor antagonist SR141716A decreases operant ethanol self administration in rats exposed to ethanol-vapor chambers. Acta Pharmacologica Sinica 20, 1109–1111.[ISI][Medline]

Shimizu, K., Matsubara, K., Uezono, T., Kimura, K. and Shiono, H. (1998) Reduced dorsal hippocampal glutamate release significantly correlates with spatial memory deficits produced by benzodiazepines and ethanol. Neuroscience 83, 701–706.[CrossRef][ISI][Medline]





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