Learning and Memory Deficits in Male Adult Mice Treated with a Benzodiazepine Sleep-Inducing Drug during the Juvenile Period.

Yusuke Furukawa,Ken-Ichi Aisaki,Kentaro Tanemura,Maky Ideta-Otsuka,Satoshi Kitajima,Katsuhide Igarashi,Masanobu Kitagawa,Jun Kanno

doi:10.3389/fnins.2016.00339

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.

Highlights

Normal brain development requires various neuronal signals must be activated at the appropriate timing and with the proper extent in the developmental brain (Rice and Barone, 2000)
We have previously reported that the transient activation of glutamate receptor (Glu-R) signals in the prenatal mouse brain with domoic acid results in aberrant emotional behavior, as well as learning and memory deficits, as revealed by a mouse behavioral battery tests (BBT) (Tanemura et al, 2009)
We stimulated the gamma-aminobutyric acid (GABA)-R signal of mice by the oral administration of the sleep-inducing drugs TZ (1 mg/kg body weight [B.W.]) or ZP (50 mg/kg B.W.) during juvenile (TZ-2w, ZP-2w) and adult stages (TZ-11w, ZP-11w)

Summary

INTRODUCTION

Normal brain development requires various neuronal signals must be activated at the appropriate timing and with the proper extent in the developmental brain (Rice and Barone, 2000). These include the open field test, the light/dark transition test, the elevated plus maze test, the contextual/cued fear conditioning test, and the pre-pulse inhibition test The results of these tests will help us to understand the effects of GABA-R signal activation during brain development with the benzodiazepine (BZD) sleep-inducing drug triazolam (TZ: original brand name “Halcion”) or the non-BZD drug zolpidem (ZP: originally marketed as “Ambien” and available worldwide under many brand names) on behavior during the adult stage (Pakes et al, 1981; Holm and Goa, 2000). The non-BZD chemical ZP binds only to combinations of GABA (A)–R α1 and γ2 subtypes (Rudolph and Knoflach, 2011)

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