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.