title: Centrally acting non-narcotic antitussives prevent hyperactivity in mice: Involvement of GIRK channels.
abstract: We have previously reported that centrally acting non-narcotic antitussives inhibited G protein-coupled inwardly rectifying potassium (GIRK) channel-activated currents, and that the antitussives had multiple pharmacological actions on various models of intractable brain diseases in rodents. In this study, the question of whether these antitussives inhibit drug-induced hyperactivity in mice was investigated. Antitussives, such as cloperastine and tipepidine, at cough suppressant doses, inhibited an increase in ambulation of mice neonatally treated with 6-hydroxydopamine. In addition, all antitussives studied inhibited an increase in methamphetamine-induced hyperactivity in mice. Methylphenidate, which is used for treatment of ADHD, inhibited 6-hydroxydopamine-lesion-induced, but not methamphetamine-induced, hyperactivity in mice. By the rota-rod test, the drugs had little effect on motor coordination of the hyperactive mice. Significant correlation was found between the ameliorating effects of antitussives on methamphetamine-induced hyperactivity and their inhibitory actions on GIRK channel currents (coefficient factor, 0.998). Furthermore, tertiapin, a GIRK channel blocker, prevented an increase in methamphetamine-induced hyperactivity of mice. These results demonstrated that antitussive drugs (cloperastine, tipepidine and caramiphen) possessing inhibitory action on GIRK channels inhibit drug-induced hyperactivity in mice, suggesting that such antitussives may potentially be therapeutic for patients with ADHD.
authors.affiliation: Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Soeda
authors.affiliation: Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujieda
authors.affiliation: Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Mizue
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shirasaki
authors.affiliation: Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. Electronic address: takahama@kumamoto-hsu.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takahama
mesh_terms: D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D006948:Hyperkinesis / Q000517:prevention & control*; D008297:Male; D051379:Mice; D011247:Pregnancy
chemical_list: D000996:Antitussive Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels
keywords: 6-OHDA; ADHD; Antitussives; GIRK channel; Hyperactivity; Methamphetamine