The behavioral effects of excitatory amino acid-induced basal forebrain lesions have been conventionally attributed to the loss of cholinergic neurons innervating cortical areas. However, comparative examinations of quisqualic acid- and ibotenic acid-induced lesions to this region have suggested that the behavioral consequences of ibotenate-induced lesions may not be exclusively related to the loss of cholinergic neurons [Etherington R. et al. (1987) Neurosci. Res. Commun. 1, 135-143; Robbins T. W. et al. (1989) Neuroscience 28, 337-352]. These findings prompted the present investigation of the effects of quisqualic acid- and ibotenic acid-induced basal forebrain lesions on cortical cholinergic fiber density and cytochrome oxidase activity. Parallel brain sections from rats with unilateral lesions produced by each toxin were examined for cytochrome oxidase activity and acetylcholinesterase-positive fiber density, at a period of four, eight and 20 days postlesion. Quisqualic acid-induced lesions resulted in a greater loss of cortical acetylcholinesterase-positive fibers than did ibotenic acid-induced lesions, but the latter lesions produced a greater reduction in cytochrome oxidase activity. These results suggest that the loss of cortical cholinergic afferents does not contribute to the cortical metabolic decrease induced by infusions of ibotenic acid into the basal forebrain. Thus, the behavioral and metabolic consequences of ibotenic acid-induced lesions may be due to the destruction of an additional, noncholinergic pathway.