Persistence of nicotinic agonist RJR 2403-induced working memory improvement in rats

Nicotinic systems are involved in the neural basis of memory function and nicotinic agonists have shown promise for the treatment of cognitive dysfunction. Both acute and chronic nicotinic treatment has been shown to improve memory performance. There is some evidence for the persistence of nicotine-induced memory improvements lasting longer than the pharmacokinetic presence of nicotine. Novel nicotinic agonists may produce the beneficial effects of nicotine on cognitive function with fewer side effects. RJR 2403 (metanicotine or (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine) a preferential alpha4beta2 nicotinic agonist has been shown in previous studies to improve memory function. The present study examined the persistence of oral RJR 2403 on memory performance in young adult Sprague-Dawley rats (3-5 months old) 30 min, 1 h, and 6 h post-administration (PO). In the first experiment, the typical inverted U-shaped dose response curve for cognitive enhancing drugs was seen with RJR 2403 30 min after administration. The lower dose of 1 mg/kg (3.6 mumol/kg), but not higher doses of 3 or 10 mg/kg (10.8 or 36 mumol/kg), of RJR 2403 significantly (P < 0.05) improved working memory on the radial-arm maze relative to placebo-treated controls. In the second experiment, young adult rats were administered RJR 2403 (0, 0.3, or 1.0 mg/kg) and tested 1 h or 6 h following administration in separate treatment groups. The 0.3 mg/kg RJR 2403 dose (1.08 mumol/kg) caused a significant (P < 0.05) memory improvement 1 h after oral administration. Interestingly, both the 0.3 and 1.0 mg/kg RJR 2403 doses (1.08 and 3.6 mumol/kg) significantly (P < 0.05) improved memory six hours after administration. These data demonstrate the efficacy of oral RJR 2403 in improving cognitive performance and the long duration of action of RJR 2403 in young adult rats. In contrast, no significant memory improvement was seen in aged rats aged (24-26 months old) after RJR 2403 administration. The inability of RJR 2403 to enhanced cognitive functions in aged rats might be related to the decrease in the number of alpha4beta2 nicotinic receptors, which occurs with age. A similar decreased responsiveness in aged rats has been seen with nicotine. The persistence of action of RJR 2403 provides additional promise for its potential as a treatment for cognitive dysfunction. However, the decreased responsiveness in subjects in populations with decreased nicotinic receptor number may limit the effectiveness of nicotinic therapies. Drug Dev. Res. 55:97-103, 2002. (C) 2002 Wiley-Liss, Inc.