Abstract
The complex pathophysiology of brain disorders and the difficulty of delivering therapeutic agents to the brain remain major obstacles in the research and development of new therapeutic methods for brain disorders. Therefore, delivering existing therapeutic agents to the central nervous system is expected to provide benefits in various diseases. In this study, we investigated whether inhaled central nervous system drugs reached the brain and affected mouse behaviour. Dizocilpine (MK-801), which increases locomotor activity in mice, was mainly used to study this hypothesis. First, we administered MK-801, an N-methyl-D-aspartate receptor antagonist, to mice via inhalation and examined whether it induced excessive activity similar to that observed after intraperitoneal administration. We also examined the time- and dose-dependency of drug induced changes in mouse behaviour after MK-801 inhalation. Next, we investigated whether inhalation of scopolamine, pentobarbital, and imipramine also affected mouse behaviour. Mice that inhaled MK-801 showed MK-801–induced hyperactivity similar to that observed following intraperitoneal administration. Furthermore, the extent of activity changed in a time- and dose-dependent manner after MK-801 inhalation. Inhalation of pentobarbital, scopolamine, and imipramine also changed mouse behaviour. These results demonstrate that inhalation of MK-801 exerts effects similar to those achieved with intraperitoneal and oral administration in mice. Thus, central nervous system agonists can reach the brain efficiently via inhalation. This finding may facilitate the development of improved therapies for brain disorders.
| Original language | English |
|---|---|
| Article number | 109038 |
| Journal | Biomedicine and Pharmacotherapy |
| Volume | 117 |
| DOIs | |
| Publication status | Published - Sep 1 2019 |
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Keywords
- Dizocilpine
- Drug
- Inhalation
- MK-801
- Mouse
- Schizophrenia
ASJC Scopus subject areas
- Pharmacology
Cite this
Behavioural effects of inhalation exposure to dizocilpine (MK-801) in mice. / Ueno, Hiroshi; Suemitsu, Shunsuke; Murakami, Shinji; Kitamura, Naoya; Wani, Kenta; Takahashi, Yu; Matsumoto, Yousuke; Okamoto, Motoi; Ishihara, Takeshi.
In: Biomedicine and Pharmacotherapy, Vol. 117, 109038, 01.09.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Behavioural effects of inhalation exposure to dizocilpine (MK-801) in mice
AU - Ueno, Hiroshi
AU - Suemitsu, Shunsuke
AU - Murakami, Shinji
AU - Kitamura, Naoya
AU - Wani, Kenta
AU - Takahashi, Yu
AU - Matsumoto, Yousuke
AU - Okamoto, Motoi
AU - Ishihara, Takeshi
PY - 2019/9/1
Y1 - 2019/9/1
N2 - The complex pathophysiology of brain disorders and the difficulty of delivering therapeutic agents to the brain remain major obstacles in the research and development of new therapeutic methods for brain disorders. Therefore, delivering existing therapeutic agents to the central nervous system is expected to provide benefits in various diseases. In this study, we investigated whether inhaled central nervous system drugs reached the brain and affected mouse behaviour. Dizocilpine (MK-801), which increases locomotor activity in mice, was mainly used to study this hypothesis. First, we administered MK-801, an N-methyl-D-aspartate receptor antagonist, to mice via inhalation and examined whether it induced excessive activity similar to that observed after intraperitoneal administration. We also examined the time- and dose-dependency of drug induced changes in mouse behaviour after MK-801 inhalation. Next, we investigated whether inhalation of scopolamine, pentobarbital, and imipramine also affected mouse behaviour. Mice that inhaled MK-801 showed MK-801–induced hyperactivity similar to that observed following intraperitoneal administration. Furthermore, the extent of activity changed in a time- and dose-dependent manner after MK-801 inhalation. Inhalation of pentobarbital, scopolamine, and imipramine also changed mouse behaviour. These results demonstrate that inhalation of MK-801 exerts effects similar to those achieved with intraperitoneal and oral administration in mice. Thus, central nervous system agonists can reach the brain efficiently via inhalation. This finding may facilitate the development of improved therapies for brain disorders.
AB - The complex pathophysiology of brain disorders and the difficulty of delivering therapeutic agents to the brain remain major obstacles in the research and development of new therapeutic methods for brain disorders. Therefore, delivering existing therapeutic agents to the central nervous system is expected to provide benefits in various diseases. In this study, we investigated whether inhaled central nervous system drugs reached the brain and affected mouse behaviour. Dizocilpine (MK-801), which increases locomotor activity in mice, was mainly used to study this hypothesis. First, we administered MK-801, an N-methyl-D-aspartate receptor antagonist, to mice via inhalation and examined whether it induced excessive activity similar to that observed after intraperitoneal administration. We also examined the time- and dose-dependency of drug induced changes in mouse behaviour after MK-801 inhalation. Next, we investigated whether inhalation of scopolamine, pentobarbital, and imipramine also affected mouse behaviour. Mice that inhaled MK-801 showed MK-801–induced hyperactivity similar to that observed following intraperitoneal administration. Furthermore, the extent of activity changed in a time- and dose-dependent manner after MK-801 inhalation. Inhalation of pentobarbital, scopolamine, and imipramine also changed mouse behaviour. These results demonstrate that inhalation of MK-801 exerts effects similar to those achieved with intraperitoneal and oral administration in mice. Thus, central nervous system agonists can reach the brain efficiently via inhalation. This finding may facilitate the development of improved therapies for brain disorders.
KW - Dizocilpine
KW - Drug
KW - Inhalation
KW - MK-801
KW - Mouse
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85066778109&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066778109&partnerID=8YFLogxK
U2 - 10.1016/j.biopha.2019.109038
DO - 10.1016/j.biopha.2019.109038
M3 - Article
VL - 117
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
SN - 0753-3322
M1 - 109038
ER -