This study aimed to investigate the effect of a single injection of pilocarpine upon the phenomenon of cortical spreading depression (SD), in adult rats submitted to early malnutrition and/or to REM-sleep deprivation for 72h prior to the SD-recordings. The SD was recorded continuously for 3-4h in 13 well-nourished (W) and 15 early-malnourished (M) adult rats. One to two hours after the beginning of the recording session, a sub-convulsing intraperitoneal (i.p.) injection of pilocarpine (190mg/kg) was applied and its effects on SD were studied during the rest of the recording session. Pilocarpine reduced markedly the ECoG amplitudes in all animals and decreased the SD velocity of propagation in the M-, but not in the W-rats, as compared with the pre-drug values for the same animals. In additional 9W- and 10 M-animals, REM-sleep deprivation was induced during the 72 h preceding the SD-recording session. This condition enhanced the pilocarpine effects on SD in the W-, but not in the M-rats, as compared to the respective non-deprived (ND) groups. The results indicate an important acute cholinergic influence on SD, acting by means of pilocarpine-activated muscarinic receptors. This effect seems to be differentially modulated by sleep deprivation and malnutrition.