Deletion of GIRK2 subunit containing GIRK channels of neurons expressing dopamine transporter decrease immobility time on forced swimming in mice

Ikutaro Honda; Kimi Araki; Sokichi Honda; Fumio Soeda; Min-Chul Shin; Shogo Misumi; Ken-Ichi Yamamura; Kazuo Takahama

doi:10.1016/j.neulet.2017.11.028

Deletion of GIRK2 subunit containing GIRK channels of neurons expressing dopamine transporter decrease immobility time on forced swimming in mice

Neurosci Lett. 2018 Feb 5:665:140-146. doi: 10.1016/j.neulet.2017.11.028. Epub 2017 Nov 24.

Authors

Ikutaro Honda¹, Kimi Araki², Sokichi Honda¹, Fumio Soeda¹, Min-Chul Shin³, Shogo Misumi¹, Ken-Ichi Yamamura⁴, Kazuo Takahama⁵

Affiliations

¹ Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
² Division of Developmental Genetics, Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
³ Faculty of Health Science, Kumamoto Health Science University, 325 Izumimachi, Kita-ku, Kumamoto 861-5598, Japan.
⁴ Yamamura Project Laboratory, Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
⁵ Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Faculty of Health Science, Kumamoto Health Science University, 325 Izumimachi, Kita-ku, Kumamoto 861-5598, Japan. Electronic address: takahama@kumamoto-hsu.ac.jp.

PMID: 29180115
DOI: 10.1016/j.neulet.2017.11.028

Abstract

We previously reported that non-narcotic antitussives possessing inhibitory actions on G protein-coupled inwardly rectifying potassium (GIRK) channels have antidepressant-like effects in the forced swimming test in normal and adrenocoticotropic hormone (ACTH) treated rats. Furthermore, the antidepressant-like effects of the antitussives such as tipepidine were blocked by dopamine D₁ receptor antagonist, and inhibitory actions on GIRK channels of dopamine neurons may be involved in the antidepressant-like effects of tipepidine. In this study, we generated GIRK2^DATKO mice with Girk2/Kcnj6 conditional deletion and assessed depression-related behavior of the mice. The Cre/loxP system was used to selectively delete GIRK2 subunit containing GIRK channels in the neurons expressing dopamine transporter. First, deletion of GIRK2 subunits in the ventral tegmental area (VTA) neurons expressing dopamine transporters was confirmed by hisitochemically and electrophysiologically. In the mice, a significant decrease in the immobility time of forced swimming test was observed. Locomotor activity of the mice was not changed compared to that of GIRK2^floxed mice, when tested in the open field. These results suggest that the antidepressant-like effect of antitussives such as tipepidine may be caused partly through the inhibitory actions on GIRK channels in the dopamine neurons.

Keywords: Antidepressant; Antitussive; GIRK2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / pharmacology
Depressive Disorder / drug therapy
Depressive Disorder / metabolism
Disease Models, Animal
Dopamine Antagonists / pharmacology
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / metabolism
G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism*
Mice, Transgenic
Swimming
Ventral Tegmental Area / drug effects*

Substances

Antidepressive Agents
Dopamine Antagonists
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Kcnj6 protein, mouse