6-OHDA lesions of the nucleus accumbens accentuate memory deficits in animals with lesions to the forebrain cholinergic projection system: effects of nicotine administration on learning and memory in the water maze.

The separate and combined effects of lesions to the forebrain cholinergic projections system (FCPS) and to dopamine (DA) terminals in the nucleus accumbens (n.acc) were assessed in two water maze tasks: (1) standard acquisition using two trials/day with a 10 min intertrial interval (ITI) for 15 days with the platform in the same position and (2) a working memory task requiring matching to a platform position located by chance on Trial 1, with four trials/day separated by a 30-s ITI and a different platform position on each of 4 days. Effects of nicotine (0.1 mg/kg) were also examined in animals with FCPS, n.acc, and combined lesions in order to determine whether facilatory effects of nicotine in FCPS lesioned animals are mediated by dopamine release in the n.acc. The FCPS and combined lesion groups were impaired in both tasks, but the combined lesion group was substantially worse than animals with FCPS lesions alone. The n.acc lesion group did not differ from controls. Nicotine did not affect acquisition in either the FCPS or combined lesion group, but impaired learning in animals with n.acc lesions. In the working memory task nicotine exerted a nonspecific facilatory effect in the FCPS and combined lesion groups, by reducing latency to find the platform both on the first trial and on the subsequent matching to position trials. Choline acetyltransferase (ChAT) activity was reduced in hippocampus and cortex in the FCPS lesion group, whereas DA levels in n.acc were increased. Conversely, in the n.acc lesion group accumbal DA levels were reduced, while cortical and hippocampal ChAT activity was increased, suggesting that reciprocal changes were induced by the separate lesions. However the combined lesion group showed mixed and more widespread effects; ChAT activity was unaltered in cortex and substantially reduced in hippocampus, and DA levels were reduced in both n.acc and caudate. The results indicate that combined FCPS and n.acc lesions impair spatial learning and working memory far more severely than FCPS lesions alone, although this does not reflect simple additive reductions in DA and ChAT activity. Nicotine improved spatial search strategy, and effect detected in the in the working memory task with daily changes in platform position, rather than in the standard acquistion task, but did not appear specifically to improve working memory. Since the facilitatory effect of nicotine was seen in both FCPS and combined lesion groups, the findings suggest that nicotine-induced improvements do not depend on accumbal DA release.