We examined the effect of intraseptal or intracerebroventricular (i.c.v.) infusions of NT-4/5 or intraseptal infusions of NGF on the level of immunohistochemical staining of choline acetyltransferase (ChAT) and the low-affinity nerve growth factor receptor (LNGFR) in the rat medial septum following unilateral transection of the fimbria. The extent of cell loss in the septum ipsilateral to the lesion, determined by cell counts of ChAT-immunopositive neurons and expressed as a ratio comparing the lesioned to the intact sides, was 0.28 in animals that received an infusion of phosphate-buffered saline (PBS). The ratios were 0.97 and 1.07 in animals that received an infusion of NT-4/5 into the ipsilateral ventricle and septum respectively. Septal infusions of NGF produced a ratio of ChAT-immunopositive cells of 1.03. The ratios of LNGFR-immunopositive neurons increased from 0.50 in PBS-infused animals to 0.79 and 0.83 in animals infused with NT-4/5 via the i.c.v. and septal routes respectively, and to 0.89 with NGF via the septal route. Transection of the fimbria also reduced the expression of TrkA in the ipsilateral medial septum and vertical limb of the diagonal band of Broca in PBS-infused animals. The loss of TrkA was ameliorated by either i.c.v. infusion of NT-4/5 or septal infusion of NT-4/5 or NGF. As determined by immunohistochemical staining, NT-4/5 infused into the lateral ventricle was detected in the periventricular portions of the forebrain ipsilateral to the infusion, while NT-4/5 or NGF infused intraseptally was detected in much of the septum, bilaterally. Furthermore, exogenous NT-4/5 or NGF was detected in numerous neuronal perikarya in the medial septal and diagonal band nuclei. These data demonstrate that, as with NGF, i.c.v. as well as septal infusions of NT-4/5 can maintain the phenotype of basal forebrain cholinergic neurons following axotomy.