Less potent in the hypnotic effect of benzodiazepine associated with decreased GABAergic transmission in the chronic social defeat stress model mouse

[Speaker] Satoshi Imai:1
[Co-author] Masaru Miyayama:1, Yuumi Shimizu:1, Nozomi Asaoka:2, Naoya Nishitani:2, Shuji Kaneko:2, Takayuki Nakagawa:1, Kazuo Matsubara:1
1:Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan, 2:Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan

BACKGROUND: 70-80% of the patients with major depressive disorder (MDD) complain of sleep disturbances. Since sleep loss is expected to exacerbate the underlying cause of MDD, it is considered that treatment of insomnia as well as depression is necessary for effective management of patients with MDD. Benzodiazepines (BZD) that strengthen inhbitory neurotransmission mediated by γ-aminobutyric acid (GABA) in the CNS are clinically effective for the treatment of sleep disturbance. However, MDD is associated with dysfunction of GABA system (Arch Gen Psyciatry, 2004). This finding suggests the possibility that BZD have less potent hypnotic efficacy in patients with MDD, but there is no undisputed evidence to support this hypothesis. Therefore, we here investigated whether the hypnotic effect of brotizolam (BZD analog) and GABAergic function in the brain are infuluenced in chronic social defeat stress (CSDS) model mice, which is a preclinical model used to study stress-induced depression.
METHODS: In CSDS paradigm, C57BL/6J mice (7 weeks old; 20-25 g) were exposed to 5 min of social defeat stress from an aggressive ICR mouse (50-70 g) for 10 consecutive days. After the last defeat, a social interaction test was carried out to select susceptible mice. The hypnotic effect of brotizolam was evaluated according to published protocol. Briefly, pentobarbital (40 mg/ml) was injected intraperitoneally 30 min after the administration of brotizolam (0.185 mg/kg, ED50), and then onset and duration time of sleep were measured. The animals were perfused and sacrificed to collect brain samples for immunohistochemistry and HPLC analysis, respectively.
RESULTS: CSDS exposure induced depression-like behaviors, characterized by increased social avoidance. The potentiation of pentobarbital-induced hypnotic effect by pre-treatment with brotizolam was significantly attenuated in CSDS mice, suggesting less potent hypnotic efficacy of brotizolam in CSDS model. We found that numbers of GABA-immunopositive neuron in the ventrolateral preoptic nucleus (VLPO) and GABA concentration in the lateral hypothalamus (LH) were reduced in CSDS mice.
CONCLUSIONS: Here, we demonstrated that the hypnotic effect of brotizolam was reduced in CSDS mice possibly as a result of the decreased GABAergic transmission from VLPO to LH.

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