In Alzheimer's disease (AD), cognitive decline is linked to cholinergic dysfunctions in the basal forebrain (BF), although the earliest neuronal damage is described in the entorhinal cortex (EC). In rats, selective cholinergic BF lesions or fiber-sparing EC lesions may induce memory deficits, but most often of weak magnitude. This study investigated, in adult rats, the effects on activity and memory of both lesions, alone or in combination, using 192 IgG-saporin (OX7-saporin as a control) and L-N-methyl-D-aspartate to destroy BF and EC neurons, respectively. Rats were tested for locomotor activity in their home cage and for working- and/or reference-memory in various tasks (water maze, Hebb-Williams maze, radial maze). Only rats with combined lesions showed diurnal and nocturnal hyperactivity. EC lesions impaired working memory and induced anterograde memory deficits in almost all tasks. Lesions of BF cholinergic neurons induced more limited deficits: reference memory was impaired in the probe trial of the water-maze task and in the radial maze. When both lesions were combined, performance never improved in the water maze and the number of errors in the Hebb-Williams and the radial mazes was always larger than in any other group. These results (i) indicate synergistic implications of BF and EC in memory function, (ii) suggest that combined BF cholinergic and fiber-sparing EC lesions may model aspects of anterograde memory deficits and restlessness as seen in AD, (iii) challenge the cholinergic hypothesis of cognitive dysfunctions in AD, and (iv) contribute to open theoretical views on AD-related memory dysfunctions going beyond the latter hypothesis.