Citicoline is an endogenous intermediate involved in the biosynthesis of brain phospholipids and acetylcholine which has been extensively used for the treatment of several neurodegenerative conditions. The effects of citicoline on neurodegeneration, apoptosis and learning were investigated in male Sprague Dawley rats subjected to implants of the beta-amyloid fragment 1-40 (A beta 4: 3 Mmol) into the right hippocampus and to permanent unilateral occlusion of the carotid artery. Citicoline (CDP; 0, 62.5, 125 and 250 mg/kg/day i.p.) was given during 2 days before and for 5 days after surgery, and the extension of the degeneration and the number of apoptotic figures (TUNEL technique) were evaluated in the dentate gyrus (DG) and the CA1 area of the hippocampus. Citicoline, at 125 and 250 mg/kg, reduced the number of apoptotic neurons in the hippocampus of rats with A beta 4/hypoperfusion-induced neurodegeneration (CDP0 = 105.3 +/- 32.8 apoptotic figures; CDP125 = 39.2 +/- 7.4** apoptotic figures; CDP250 = 34.5 +/- 14.4** apoptotic figures; **p < 0.01 vs. CDP0). CDP also reduced neuronal degeneration in the CA1 area in a dose-dependent manner (CDP0 = 450.5 +/- 130.1 microns; CDP62.5 = 280.6 +/- 76.3 microns; CDP125 = 86.6 +/- 37.3* microns; CDP250 = 121.7 +/- 85.3* microns; p < 0.05 vs. CDP0). Variability of results was very high in the DG, where a significant reduction in the extent of neurodegeneration was only observed in the group of rats receiving 62.5 mg/kg of citicoline. Finally, citicoline improved retention of a passive avoidance learning task, increasing the number of avoidances (Av) (CDP0 = 4.2 +/- 0.7 Av; CDP62.5 = 6.9 +/- 1.0 Av; CDP125 = 7.9 +/- 0.7** Av; CDP250 = 8.5 +/- 0.6** Av; **p < 0.01 vs. CDP0) in a dose-related manner. Based on these results, it was concluded that citicoline exerts antiapoptotic, neuroprotective and antiamnesic effects in conditions of neurodegeneration induced by A beta 4 plus hypoperfusion.