Targeted mutation of CCK2 receptor gene modifies the behavioural effects of diazepam in female mice |
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Authors: | Raud Sirli Rünkorg Kertu Veraksits Alar Reimets Ain Nelovkov Aleksei Abramov Urho Matsui Toshimitsu Bourin Michel Volke Vallo Kõks Sulev Vasar Eero |
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Institution: | (1) Department of Physiology, Biomedicum, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia;(2) Division of Hematology/Oncology, Department of Medicine, Kobe University School of Medicine, 650-0017 Kobe, Japan;(3) Department of Pharmacology, University of Nantes, 44035 Nantes Cedex, France |
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Abstract: | Rationale Evidence suggests that GABA and CCK have opposite roles in the regulation of anxiety.
Objective The aim of the present work was to study diazepam-induced anxiolytic-like action and impairment of motor co-ordination, and
the parameters of benzodiazepine receptors in mice lacking CCK2 receptors.
Methods The action of diazepam (0.5–3 mg/kg IP) was studied in the elevated plus-maze model of anxiety and rotarod test using mice
lacking CCK2 receptors. The parameters of benzodiazepine receptors were analysed using 3H]-flunitrazepam binding.
Results In the plus-maze test, the exploratory activity of the homozygous (−/−) mice was significantly higher compared to their wild-type
(+/+) littermates. However, the wild-type (+/+) mice displayed higher sensitivity to the anxiolytic-like action of diazepam.
Even the lowest dose of diazepam (0.5 mg/kg) induced a significant increase of open arm entries in the wild-type (+/+) mice.
A similar effect in the homozygous (−/−) mice was established after the administration of diazepam 1 mg/kg. The highest dose
of diazepam (3 mg/kg) caused a prominent anxiolytic-like effect in the wild-type (+/+) mice, whereas in the homozygous (−/−)
animals suppression of locomotor activity was evident. The performance of the homozygous (−/−) mice in the rotarod test did
not differ from that of the wild-type (+/+) littermates. However, a difference between the wild-type (+/+) and homozygous
(−/−) animals became evident after treatment with diazepam. Diazepam (0.5 and 3 mg/kg) induced significantly stronger impairment
of motor co-ordination in the homozygous (−/−) mice compared to their wild-type (+/+) littermates. The density of benzodiazepine
binding sites was increased in the cerebellum, but not in the cerebral cortex and hippocampus, of the homozygous (−/−) mice.
Conclusions Female mice lacking CCK2 receptors are less anxious than their wild-type (+/+) littermates. The reduced anxiety in homozygous (−/−) mice probably
explains why the administration of a higher dose of diazepam is necessary to induce an anxiolytic-like action in these animals.
The highest dose of diazepam (3 mg/kg) induced significantly stronger suppression of locomotor activity and impairment of
motor co-ordination in the homozygous (−/−) mice compared to the wild-type (+/+) littermates. The increase in the action of
diazepam is probably related to the elevated density of benzodiazepine receptors in the cerebellum of homozygous (−/−) mice.
The present study seems to be in favour of increased tone of the GABAergic system in mice without CCK2 receptors. |
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Keywords: | Targeted mutagenesis Wild-type Heterozygous Homozygous Benzodiazepine receptors GABA Diazepam Cholecystokinin Cholecystokinin2 receptors Rotarod test Motor co-ordination Elevated plus-maze Exploratory behaviour Anxiety |
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