An antihyperkinetic action by the serotonin 1A-receptor agonist osemozotan co-administered with psychostimulants or the non-stimulant atomoxetine in mice.
It has been demonstrated that treatment of hyperactive mice with psychostimulants produced a calming effect depending on serotonergic neurotransmission. Our previous study also showed that hyperactivity in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) was ameliorated by amphetamine in a serotonin (5-HT)(1A)-dependent manner and that amphetamine calmed wild-type mice given the 5-HT(1A) agonist 8-OH-DPAT. Here, we examined if 5-HT(1A)-mediated pathways can be a determinant of the action of other psychostimulants as well as the non-stimulant atomoxetine by examining locomotor activity in mice co-administered with the 5-HT(1A) agonist osemozotan. Co-administration of osemozotan with either methamphetamine or amphetamine was not only antihyperkinetic, but also decreased locomotion to below basal levels. In contrast, osemozotan just nullified methylphenidate-induced hyperactivity. The non-stimulant atomoxetine did not induce hyperactivity, but co-administration of atomoxetine with osemozotan produced a calming effect. The adjunctive effect of osemozotan added to the psychostimulants was blocked by the 5-HT(1A) antagonist WAY-100635 at a low dose (0.1 mg/kg), suggesting the involvement of a presynaptic 5-HT(1A)-mediated mechanism. However, WAY-100635 (up to 1 mg/kg) did not block the effect of atomoxetine plus osemozotan. The present results may provide insights into the therapeutic mechanisms of the psychostimulants and atomoxetine for hyperkinetic disorders.
Tsuchida
Rie
R
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
Kubo
Masahiro
M
Kuroda
Mariko
M
Shibasaki
Yasuhiro
Y
Shintani
Norihito
N
Abe
Michikazu
M
Köves
Katalin
K
Hashimoto
Hitoshi
H
Baba
Akemichi
A
D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology*; D004149:Dioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006948:Hyperkinesis / Q000188:drug therapy*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011437:Propylamines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D004146:Dioxanes; D004149:Dioxoles; D010879:Piperazines; D011437:Propylamines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D008694:Methamphetamine; D000069445:Atomoxetine Hydrochloride; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000661:Amphetamine; C096294:osemozotan