DIFFERENCES IN ETHANOL INGESTION BETWEEN CHOLECYSTOKININ-A RECEPTOR DEFICIENT AND -B RECEPTOR DEFICIENT MICE

KYOKO MIYASAKA*, HIROKO HOSOYA, SAEKO TAKANO, MINORU OHTA, AYAKO SEKIME, SETSUKO KANAI, TOSHIMITSU MATSUI1 and AKIHIRO FUNAKOSHI2

Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho Itabashiku, Tokyo 173-0015, Japan, 1 Third Division, Department of Medicine, Kobe University School of Medicine, Kobe 650-0017, Japan and 2 Division of Gastroenterology, National Kyushu Cancer Center, Fukuoka 811-1395, Japan

* Author to whom correspondence should be addressed: Kyoko Miyasaka, Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho Itabashiku, Tokyo 173-0015, Japan. Tel.: +81 3964 3241 (ext. 3088); Fax: +81 3579 4776; E-mail: miyasaka{at}tmig.or.jp

(Received 13 July 2004; first review notified 29 September 2004; accepted in revised form 17 February 2005; Advance Access publication 14 March 2005)


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: Cholecystokinin (CCK) modulates dopamine release in the nucleus accumbens through the CCK-A receptor (CCK-AR). The dopaminergic neurotransmission between the ventral tegmental area and the limbic forebrain is a critical neurobiological component of alcohol and drug self-administration. Based on the evidence of interaction between CCK and dopamine, we had found previously that the CCK-AR gene –81A/G polymorphism was associated with alcohol dependence. Since the precise mechanism underlying this association has not been elucidated, the role of CCK-AR in ethanol ingestion was examined using CCK-AR gene deficient (–/–) mice and compared with those of CCK-BR(–/–) and wild-type mice. Methods: The two-bottle choice protocol was conducted and the righting reflex was examined in these three genotypes. Furthermore, the protein level of dopamine 2 receptor (D2R) in the nucleus accumbens was determined by western blotting. Results: CCK-AR(–/–) mice consumed more ethanol than CCK-BR(–/–) and wild-type mice, and showed no aversion to high concentrations of ethanol solution. However, the difference was actually in the total fluid consumption and alcohol preference remained unchanged, indicating that the differences were not specific to alcohol. Behavioral sensitivity to ethanol, examined using the righting reflex, did not differ significantly between the groups. D2R expression in the nucleus accumbens was significantly lower in the CCK-BR(–/–) mice and was significantly higher in CCK-AR(–/–) mice than in wild-type mice. Conclusions: Voluntary ingestion of ethanol differed between CCK-AR(–/–) and CCK-BR(–/–) mice. The difference might be attributable in part to the different levels of D2R expression in the nucleus accumbens.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cholecystokinin (CCK), one of the most abundant neurotransmitter peptides in the brain, is known to interact with dopamine (Crawley, 1991Go; Marshall et al., 1991Go; Woodruff et al., 1991Go; Ladurelle et al., 1994Go; Hamilton and Freeman, 1995Go). The dopaminergic neurotransmission between the ventral tegmental area and the limbic forebrain is a critical neurobiological component of the self-administration of alcohol and drugs (Kalivas, 1993Go; Self and Nestler, 1995Go). CCK coexists in the mesolimbic dopamine neurons, and CCK-A receptor (CCK-AR) mediates the release of dopamine in the nucleus accumbens (Crawley, 1991Go; Marshall et al., 1991Go; Woodruff et al., 1991Go; Ladurelle et al., 1994Go; Wank, 1995Go; Hamilton and Freeman, 1995Go).

We had previously investigated the association between the CCK-AR gene polymorphism (Funakoshi et al., 2000Go) and alcohol dependence in humans, and found that the CCK-AR gene –81A/G polymorphism was associated with alcohol dependence in a Japanese population (Miyasaka et al., 2004Go). Our recent investigation using the STC-1 murine neuroendocrine cell line showed that the –81A to G change decreased luciferase activities only slightly (not significantly) (Takata et al., 2002Go). However, limitations in the experimental conditions suggest that those findings should be interpreted as inconclusive, because no human cell lines expressing CCK-AR are available.

Since we speculated that the –81A/G polymorphism might decrease the CCK-AR gene expression, in the present study, the role of CCK-AR in ethanol ingestion was examined using CCK-AR gene deficient (–/–) mice (Suzuki et al., 2001Go; Takiguchi et al., 2002Go). The two-bottle choice protocol was conducted and the righting reflex was examined. Two types of CCK receptors (CCK-AR and -BR) have been cloned so far (Wank, 1995Go). Although CCK-BR is widely distributed throughout the central nervous system, CCK-AR is found in specific regions, such as the amygdala, nucleus tractus solitarius, posterior nucleus accumbens, ventral tegmental area, substantia nigra and raphe nucleus. Furthermore, the amino acid sequence of rat CCK-BR is 48% identical to that of rat CCK-AR (Wank, 1995Go), and the expression patterns of these receptors overlap in the brain (Hill et al., 1987Go; Hughes et al., 1990Go; Honda et al., 1993Go). Although several pharmacological studies using CCK receptor antagonists have been reported (Hughes et al., 1990Go; Wank, 1995Go), cross-reactivity, in which substances that should react to CCK-AR also react to CCK-BR and vice versa, could not be excluded. Therefore, to determine the physiological role of CCK-AR more conclusively, we used CCK-AR(–/–) and BR(–/–) mice (Nagata et al., 1996Go, Miyasaka et al., 2002Go) as well as wild-type mice. These three types of mice are viable and are fertile into adulthood. Furthermore, the protein levels of dopamine 2 receptor (D2R) in the nucleus accumbens of these mice were determined by western blotting, because signaling through D2R has been known to govern physiological functions related to locomotion and drug abuse (Maldonado et al., 1997Go; Usiello et al., 2000Go), and because D2R was expressed highly in the striatal complex, where CCK-AR and BR were expressed.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals
The protocol was reviewed and approved by the appropriate committee of the Tokyo Metropolitan Institute of Gerontology.

The progenitor strain for CCK-AR(–/–) and BR(–/–) was C57BL/6J (Nagata et al., 1996Go; Takiguchi et al., 2002Go). More than seven generations of backcrossing have been performed. Mice were fed commercial chow (CRF-1: Charles River Japan Inc., Yokohama). We used age-matched (8–10 months) male mice in the test. The animals were maintained in individual cages in an air-conditioned room at 21°C, with 55 ± 5% humidity, and with a 12-h light/dark photocycle (8 am–8 pm) at the Tokyo Metropolitan Institute of Gerontology. The cage size was 18 x 30 x 11 cm.

Two-bottle choice protocol
The two-bottle choice protocol consisted of four cycles of 7 days each, with the animals having access to 3, 6, and 10% ethanol successively, always versus tap water. Subsequently, some of the wild-type mice were given access to 20% ethanol, and others were used for the examination of the righting reflex as described below. Fluid consumption and body weight were evaluated by measuring fluid volumes at 3 pm every Monday. The places of the two bottles were reversed relative to each other on each Wednesday and Friday. The mean body weight during each 7-day period was estimated, and fluid consumption/kg mean body wt was estimated.

For comparison, additional mice were offered saccharin (0.033%) and quinine (0.03 mM) each versus tap water.

Righting reflex
Mice (without overnight fasting) were given an i.p. injection of 4.5 g/kg ethanol solution (30%) between 10 and 11 am. A mouse was judged to have recovered the righting reflex if it righted itself successfully twice within 30 s after being turned upside down two times at each of the several scheduled times after the administration (Haseba et al., 1993Go). Scoring was as follows: no recovery = 0, recovery the first time but not the second = 1, successful both times but without walking = 2, and awake and walking = 3.

Determination of DR2 by western blotting
Three additional animals for each genotype were decapitated between 10 and 11 am without any treatment, and the whole brain was immediately removed. The nucleus accumbens was quickly dissected and then stored at –80°C for later experiments. Each tissue sample was separately homogenized in lysis buffer. Synaptic plasma membrane was isolated according to the method of Jones and Matus (1974)Go.

The respective nucleus accumbens homogenates (100 Mg of protein) were separated on a sodium dodecyl sulfate–7.5% polyacrylamide gel. The proteins were electrophoretically transferred on to a polyvinylidene difluoride (PVDF) membrane (Bio-Rad Laboratories, Hercules, CA) and then blocked with 5% skim milk for 1 h at room temperature.

The membrane was incubated with the goat anti-human D2R(L/S) antibody (1:250; Alpha Diagnostics International, San Antonio, TX) overnight at 4°C. After three washes, the membrane was incubated with 1:15 000 horseradish peroxidase-linked secondary anti-goat IgG (H+L) antibody for 1 h at room temperature. After three further washes, immunoreactive bands were detected using the Enhanced Chemiluminescence assay system (ECL Plus, Amersham Biosciences, Buckinghamshire, UK) (Rogers et al., 1991Go).

Autoradiograms then underwent a semiquantitative densitometric analysis. The data were expressed as means ± SE. The optical density (OD) of the immunoreactive bands was calculated by using an NIH Image software package.

Statistical analysis
Results were analyzed by multiple analysis of variance (MANOVA) with repeated measures or by one-way ANOVA, followed in either case by Fisher's protected least significant difference (PLSD). P < 0.05 was considered to be significant.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ethanol consumption
The changes in mean body weight during ethanol drinking did not differ between CCK-AR(–/–), BR(–/–), and wild-type mice (Fig. 1).



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Fig. 1. Changes in mean body weight. The calculation method is described in the text. There were no significant differences between genotypes or with respect to ethanol concentration. n = 28 for wild-type, 19 for CCK-AR(–/–) and 10 for CCK-BR(–/–) mice.

 
The mean values of the total volume consumed (the sum of water and ethanol solution) were significantly higher in CCK-AR(–/–) mice than in CCK-BR(–/–) and wild-type mice throughout the experimental period (Fig. 2). The mean values of the consumed volume of ethanol solution tended to be higher in CCK-AR(–/–) mice than in the other genotypes (Fig. 2). The ingestion volume of 20% ethanol solution was decreased in wild-type mice relative to the other concentrations, and the volumes of 10 and 20% ethanol solutions were decreased in CCK-BR(–/–) mice relative to the other concentrations. However, there was no decrease in the ingestion volume of ethanol solution in CCK-AR(–/–) mice, irrespective of the concentration (Fig. 2).



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Fig. 2. Changes in total fluid consumption/kg body wt. Open symbols represent total fluid consumption and closed marks represent consumed volume of ethanol. The total fluid consumption was significantly different between genotypes when analyzed by MANOVA (F = 6.82, P = 0.002), and the values for CCK-AR(–/–) mice were significantly higher than those of other genotypes when analyzed by Fisher's PLSD. The numbers of animals are the same as in Fig. 1.

 
According to the differences between the genotypes in the volume of ethanol solutions consumed, absolute ethanol consumption was highest in CCK-AR(–/–) mice and lowest in CCK-BR(–/–) mice. To elaborate, CCK-AR(–/–) mice consumed significantly higher ethanol than wild-type mice when 6 or 20% ethanol was supplied, and CCK-BR(–/–) consumed significantly less ethanol than CCK-AR(–/–) mice when 10% ethanol was supplied (Fig. 3). However, ethanol preference ratios (ethanol volume/total volume) in CCK-AR(–/–) mice did not significantly change with respect to the different ethanol concentrations (Table 1).



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Fig. 3. Ethanol consumption/kg body wt. There were significant differences between genotypes when analyzed by MANOVA (F = 3.17, P = 0.046). *Significantly different from the value of wild-type mice; and {dagger}significantly different from the value of CCK-AR(–/–) mice analyzed by Fisher's PLSD. The numbers of animals are the same as in Fig. 1.

 

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Table 1. Ethanol preference ratio (ethanol volume/total volume)

 
Saccharin and quinine consumption
In contrast, there were no significant differences in the intake of saccharin (sweet) or quinine (bitter) solutions (Table 2). Mice prefer sweet solutions and avoid bitter solutions irrespective of the genotype. Water consumption did not differ between the genotypes. The total volume consumed by CCK-BR(–/–) mice tended to be lower than that in CCK-AR(–/–) and wild-type mice, but not significantly. Body weight during experimental periods did not differ between the groups.


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Table 2. Fluid consumption of saccharin (0.033%) and quinine (0.3 mM) in CCK-AR(–/–), BR(–/–) and wild-type mice (ml/kg body wt/day)

 
Righting reflex in response to an acute i.p. dose of ethanol (4.5 g/kg)
There were no significant differences between CCK-AR(–/–), BR(–/–) and wild-type mice when analyzed by repeated measures MANOVA (Fig. 4). The value at 90 min in CCK-BR(–/–) mice was significantly lower compared with the other two genotypes when analyzed by one-way ANOVA.



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Fig. 4. Righting reflex scores after injection of 4.5 g/kg body wt of ethanol into the abdominal cavity. There were no significant differences between genotypes when analyzed by MANOVA (F = 1.37, P = 0.27). n = 12 for wild-type, 19 for CCK-AR(–/–) and 10 for CCK-BR(–/–) mice.

 
D2R expression in the nucleus accumbens
The protein level of D2R in the nucleus accumbens was significantly higher in CCK-AR(–/–) mice than in wild-type mice (Fig. 5, left panel). In contrast, the D2R expression was significantly lower in CCK-BR(–/–) than in wild-type mice (Fig. 5, right panel).



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Fig. 5. Western blotting in CCK-AR(–/–), CCK-BR(–/–) and wild-type mice.

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The present investigation showed that CCK-AR(–/–) mice consumed more ethanol than CCK-BR(–/–) and wild-type mice. However, the difference was actually in the total fluid consumption and alcohol preference remained unchanged, indicating that the differences were not specific to alcohol. In contrast, in the case of a choice between saccharin (or quinine) and tap water, the total volume consumed was lower in CCK-BR(–/–) mice than in CCK-AR(–/–) and wild-type mice, but the difference was not significant. There were no differences between CCK-AR(–/–) and wild-type mice either. Therefore, the choice between saccharin (or quinine) and water was not determined in the same way as the choice between alcohol and tap water, although the precise mechanism is unknown. Ethanol sensitivity, as examined by the righting reflex in response to an acute i.p. dose of ethanol (4.5 g/kg), did not differ significantly between the groups, although the score at 90 min was low in CCK-BR(–/–) mice.

Experiments with rodents have provided considerable evidence that dopamine is involved in the self-administration of ethanol (Lanca et al., 1994Go; Phillips et al., 1998Go). However, there has been a controversy concerning the role of dopamine in alcohol preference in rodents. In a previous report (George et al., 1995Go), a low availability of synaptic dopamine was postulated to increase ethanol preference. In contrast, Phillips et al. (1998)Go reported that alcohol preference and sensitivity are reduced in D2R(–/–) mice. In the present study, we observed that CCK-BR(–/–) mice showed a significant decrease in D2R protein expression in the nucleus accumbens, and they ingested less ethanol; in particular, their consumption of 10% ethanol was significantly lower than that of CCK-AR(–/–) mice. Thus, our present observation was compatible with that of Phillips et al. (1998)Go, in which lower D2R function decreased the voluntary ingestion of ethanol.

On the other hand, CCK-AR(–/–) mice showed an increase in D2R expression and showed no aversion to the high concentrations of ethanol, although the preference ratio did not increase. There have been controversial reports on the phenotype of D2R(–/–) mice (Baik et al., 1995Go; Kelly et al., 1997Go). Baik et al. (1995)Go reported that D2R(–/–) mice showed reduced food and water intake as well as retarded growth, whereas Kelly et al. (1997)Go did not observe any inhibition in the gain of body weight. In recent reports (Usiello et al., 2000Go; Wang et al., 2000Go), D2R has been shown to have two isoforms, a long form (D2R-L) and a short form (D2R-S). D2R-L was strongly expressed in the striatum and nucleus accumbens (Khan et al., 1998Go). D2R-L (–/–) mice displayed reduced levels of locomotion and rearing behavior (Wang et al., 2000Go). We have previously observed (Miyasaka et al., 2002Go) that locomotor activity was increased in CCK-AR(–/–) mice and was decreased in CCK-BR(–/–) mice in a plus maze. Since an animal model with overexpressed D2R has not been available, it is unknown whether the increase in D2R level has an essential role in the increase of locomotor activity. Taken together, these findings suggest that although the mechanism underlying CCK-Rs modulation of D2R expression is unknown, the differences in ethanol ingestion between CCK-AR(–/–) and BR(–/–) mice might be related to the D2R expression level.

In summary, voluntary ingestion of ethanol differed between CCK-AR(–/–) and CCK-BR(–/–) mice. This difference might be attributable to the different levels of D2R expression in the nucleus accumbens between these genotypes.


    ACKNOWLEDGEMENTS
 
This study was supported in part by Grants-in-Aid for Scientific Research (B-15390237 and 14657107, to K.M.) from the Ministry of Education, Culture, Sports, Science and Technology, a grant from the Pancreas Research Foundation of Japan (K.M.), a Research Grant for Comprehensive Research on Aging and Health (10C-4, to K.M.) from the Ministry of Health, Labour and Welfare, and a Grant-in-Aid for Cancer Research (16-15) from the Ministry of Health and Welfare of Japan (A.F.).


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