Interactions between the effects of propranolol and nicotine on radial maze performance of rats with lesions of the forebrain cholinergic projection system

This experiment investigated the hypothesis that nicotine-induced regional release of noradrenaline contributes to the improvements in radial maze performance following nicotine treatment in rats with lesions to the forebrain cholinergic projection system (FCPS), by examining whether pretreatment with the noradrenergic beta-receptor antagonist propranolol abolished the facilitative effects of nicotine. After S-AMPA (8.0mM) lesions to the nuclei of origin of the FCPS in the nucleus basalis and medial septal areas, rats displayed long-lasting impairment in long-term reference and short-term working memory in both spatial (place) and associative (cue) radial maze tasks. Performance of control and lesioned rats was assessed after administration of nicotine (0.1mg/kg), propranolol (either 0.5 or 5.0mg/kg) and both treatments. Nicotine reduced working memory error rates in lesioned animals, but did not affect the performance of controls. Propranolol dose-relatedly increased error rates in both control and lesioned animals. Adverse effects were more marked in controls, all four types of error being increased under the high dose of propranolol, whereas in lesioned rats significant increases in error rates above baseline were confined to working memory. The low dose of propranolol, in conjunction with nicotine, abolished the improvement in working memory seen with nicotine alone in lesioned rats. However, under joint treatment with the high dose, the substantial increases in working memory error rates seen in lesioned rats after propranolol alone were reduced to baseline level. In controls, reduction in errors to baseline was seen only in the cue task; place task errors remained significantly elevated. These results suggest that both cholinergic depletion and noradrenergic blockade exert disruptive effects on cognition, but that these effects are largely independent, since an additive or interactive mechanism would be predicted to produce greater disruption, following noradrenergic blockade, in lesioned rather than in control animals. Although facilitative effects of nicotine were abolished with the low dose of propranolol, the results further suggest that these effects are independent of release of noradrenaline, since nicotine continued to reduce errors in control and lesioned animals following blockade of beta receptors with the high dose of propranolol.