This study examined the behavioral effects of maximal doses of exogenous NGF and/or GM1 when given intracerebroventricularly to adult rats with unilateral cortical lesions. In addition, the long-term effects of these agents on choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) activity, and choline uptake, as well as on ChAT and NGF receptor (p75NGFR) immunoreactivity in various brain regions, were also investigated. When retested in passive avoidance and Morris water maze tasks, 30 days postlesion (i.e., 2 weeks after termination of treatment), decorticated vehicle-treated rats showed retention and reacquisition deficits which were equally attenuated by NGF (6 micrograms/day, 14 days) or NGF + GM1 (750 micrograms/day, 14 days) treatment. By contrast, lesioned animals which received GM1 alone only showed improved reacquisition of the two tasks. After behavioral testing (52 days postlesion) lesioned vehicle-treated animals had decreased ChAT activity in the ipsilateral nucleus basalis magnocellularis (NBM) but not in other subcortical brain areas examined. Neuronal loss was observed only in the ventrolateral nucleus of the ipsilateral dorsal thalamus. However, using quantitative image analysis a significant shrinkage of ChAT immunoreactive (IR) and p75NGFR-IR NBM neurons as well as a decrease in their neuritic network was noted, particularly in the mid portion of the NBM. GM1 and NGF equally prevented these deficits in the NBM and, furthermore, enhanced ChAT activity and choline uptake in the remaining cortex ipsilateral to the lesion site. These alterations in NBM and cortical cholinergic markers were even more augmented in rats which received both NGF and GM1 treatment. By contrast, the noted NGF-induced increase in striatal ChAT activity was not further increased by concomitant GM1 treatment. GAD activity in all brain areas examined was unaltered by the lesion or any of the treatments and the apparent thalamic neuronal retrograde degeneration was not prevented by any of the treatments. It is concluded that GM1 or NGF treatment can distinctly affect performance of cortically lesioned rats in passive avoidance and Morris water maze tasks despite their equal ability to serve as long-term neuroprotective agents for the basalo-cortical cholinergic pathway.