The present experiment examined whether p-chloroamphetamine (PCA), a serotonergic releasing/depleting agent, would block the memory-enhancing effect of physostigmine in rats with N-methyl-D-aspartic acid (NMDA)-induced unilateral lesions of the nucleus basalis of Meynert (uni-nbM). Six groups of subjects with uni-nbM lesions in addition to an isolated sham-operated control group were included. Subjects were trained and tested 72 h later on a one-trial passive avoidance task. Thirty minutes before training, rats with uni-nbM lesions were injected with either 1.0 or 5.0 mg/kg PCA or saline. Immediately after training, approximately half the subjects in each group were injected with either saline or 0.06 mg/kg physostigmine. Animals in the sham group received saline injections. Saline-injected animals with uni-nbM lesions performed poorly at test, a deficit that was reversed with physostigmine. Pretraining injections of PCA blocked physostigmine's memory-enhancing effect, although motor impairment during training may have contributed to decrements in test performance in animals injected with 5.0 mg/kg. Subjects were killed about 10 days later and their frontal cortices examined for choline acetyltransferase (ChAT). Results from the neurochemical analysis revealed that the lesion decreased ChAT levels and that the injection of 1.0 mg/kg PCA exaggerated this lesion-induced depletion. Implications for the interaction between acetylcholine and serotonin are discussed.