Differences in ethanol ingestion between cholecystokinin-A receptor deficient and -B receptor deficient mice.
OBJECTIVE
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.
Miyasaka
Kyoko
K
Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. miyasaka@tmig.or.jp
Hosoya
Hiroko
H
Takano
Saeko
S
Ohta
Minoru
M
Sekime
Ayako
A
Kanai
Setsuko
S
Matsui
Toshimitsu
T
Funakoshi
Akihiro
A
D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D004334:Drug Administration Schedule; D000431:Ethanol / Q000008:administration & dosage; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D043886:Receptor, Cholecystokinin A / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D043887:Receptor, Cholecystokinin B / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis
D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D017448:Receptors, Dopamine D2; D000431:Ethanol