title: Alpha4beta2 nicotinic acetylcholine receptor activation ameliorates impairment of spontaneous alternation behavior in stroke-prone spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder.
abstract: The objective of the present study was to elucidate the role of nicotine in impairment of spontaneous alternation behavior of juvenile stroke-prone spontaneously hypertensive rats (SHRSP), an animal model of attention deficit hyperactivity disorder (ADHD). Spontaneous alternation behavior assessed by a Y-maze task was significantly lower, and total arm entries were significantly higher in SHRSP than in genetic control Wistar-Kyoto rats. Nicotine (0.1-1 mg/kg, s.c.) dose dependently improved the spontaneous alternation deficit without affecting total arm entries in SHRSP. Nicotine-induced (1 mg/kg, s.c.) improvement was significantly abolished by the centrally acting nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (1 mg/kg, i.p.), but not by peripherally acting hexamethonium (5 mg/kg, i.p.), suggesting that nicotine-induced improvement is mediated via central nAChR. The alpha4beta2 nAChR antagonist dihydro-beta-erythroidine (3-10 mg/kg, i.p.) dose dependently counteracted nicotine-induced improvement of spontaneous alternation in SHRSP, whereas the alpha7 nAChR antagonist methyllycaconitine (3-10 mg/kg, i.p.) did not. In addition, the alpha4beta2 nAChR agonist RJR-2403 (N-methyl-4-(3-pyridinyl)-3-butene-1-amine; 1-10 mg/kg, s.c.) dose dependently and significantly improved the spontaneous alternation deficit. These findings revealed that nicotine improved spontaneous alternation behavior in SHRSP via the activation of alpha4beta2, but not alpha7, nAChR. Thus, the alpha4beta2 nAChR mechanism might be responsible for the spontaneous alternation deficit in juvenile SHRSP, an animal model of ADHD. This evidence indicates the possibility that selective alpha4beta2 nAChR agonists might be useful for treating attentional dysfunction in ADHD.
authors.affiliation: Department of Pharmacology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. ken-ueno@med.hokudai.ac.jp
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Ueno
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togashi
authors.forename: Machiko
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohashi
authors.forename: Hideya
authors.initials: H
authors.lastname: Saito
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshioka
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018738:Hexamethonium / Q000494:pharmacology; D006973:Hypertension / Q000235:genetics* / Q000523:psychology*; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017933:Peripheral Nervous System / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011978:Receptors, Nicotinic / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D002491:Central Nervous System Agents; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D004079:Dihydro-beta-Erythroidine; D018738:Hexamethonium; D008464:Mecamylamine; D009538:Nicotine