Linopirdine (DuP996) facilitates the retention of avoidance training and improves performance of septal-lesioned rats in the water maze.

The behavioral effects of 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one [linopirdine (DuP996)] were investigated on retention of the inhibitory avoidance test in normal mice and acquisition of spatial discrimination in the two-platform water maze task in septal-lesioned rats (a model of cholinergic dysfunction characteristic of Alzheimer's disease). Linopirdine significantly enhanced retention of the inhibitory avoidance response in mice (0.026 mumol/kg) and also reduced the number of errors made by septal-lesioned rats in the water maze to a level comparable to sham-operated animals. At this dose, no effects were observed on septal-lesion-induced hyperactivity in an open field or in unoperated rats tested in the elevated plus-maze anxiolytic test. This study extends previous findings of facilitatory effects of linopirdine on memory and demonstrates improved spatial learning in septal-lesioned rats. As the facilitatory effects on memory are not accompanied by a reduction in the hyperactive state present in septal-lesioned animals, a dissociation between cognitive and noncognitive effects of linopirdine can be differentiated in septal-lesioned rats.