title: Learning and Memory Deficits in Male Adult Mice Treated with a Benzodiazepine Sleep-Inducing Drug during the Juvenile Period.
abstract: Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R) mediated signaling (GABA-R signal) during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ) or the non-benzodiazepine drug zolpidem (ZP). We detected learning and memory deficits in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs), which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible learning and memory deficits in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause learning and memory deficits.
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health SciencesTokyo, Japan; Department of Comprehensive Pathology, Graduate School, Tokyo Medical and Dental UniversityTokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University Sendai, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tanemura
authors.affiliation: Life Science Tokyo Advanced Research Center, Hoshi University School of Pharmacy and Pharmaceutical Sciences Tokyo, Japan.
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Life Science Tokyo Advanced Research Center, Hoshi University School of Pharmacy and Pharmaceutical Sciences Tokyo, Japan.
authors.forename: Maky
authors.initials: M
authors.lastname: Ideta-Otsuka
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences Tokyo, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Aisaki
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitajima
authors.affiliation: Department of Comprehensive Pathology, Graduate School, Tokyo Medical and Dental University Tokyo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kitagawa
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health SciencesTokyo, Japan; Japan Bioassay Research Center, Japan Organization of Occupational Health and SafetyHadano, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
keywords: GABA receptor signal; behavioral battery test; sleep-inducing drug; triazolam; zolpidem