Vol. 302, Issue 1, 95-100, July 2002

42 Nicotinic Acetylcholine Receptor Activation Ameliorates Impairment of Spontaneous Alternation Behavior in Stroke-Prone Spontaneously Hypertensive Rats, an Animal Model of Attention Deficit Hyperactivity Disorder

Ken-ichi Ueno, Hiroko Togashi, Machiko Matsumoto, Satoshi Ohashi, Hideya Saito and Mitsuhiro Yoshioka

Department of Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (K.-i.U., H.T., M.M., S.O., M.Y.); and Department of Basic Sciences, Japanese Red Cross Hokkaido College of Nursing, Kitami, Japan (H.S.)

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 42 nAChR antagonist dihydro--erythroidine (3-10 mg/kg, i.p.) dose dependently counteracted nicotine-induced improvement of spontaneous alternation in SHRSP, whereas the 7 nAChR antagonist methyllycaconitine (3-10 mg/kg, i.p.) did not. In addition, the 42 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 42, but not 7, nAChR. Thus, the 42 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 42 nAChR agonists might be useful for treating attentional dysfunction in ADHD.