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Neurons in the rat frontal cortex demonstrate altered firing rates in response to conditioned stimuli. Experiments were designed to test the hypothesis that the basal forebrain cholinergic systera is involved in the generation of conditioned neuronal responses in the rat frontal cortex. Most of the cholinergic innervation to the frontal cortex is supplied by projections frora the nucleus basalis raagnocellularis (nBM), A two-second tone cue imraediately followed by rewarding medial forebrain bundle stimulation was used to elicit the conditioned neuronal responses in the following experiraents. Experiment One was performed to determine the effects of inhibiting the firing of neurons in the nBM region on the conditioned responses. This was presuraably accomplished by microinjecting procaine, a local anesthetic, or GABA, an inhibitory neurotransraitter, into the nBM region. Procaine antagonized the conditioned responses of 86% of the cortical single units tested and GABA antagonized the responses of 81% of the units. Experiment Two was designed to investigate the effects of blocking cholinergic receptors on the conditioned responses of frontal cortex neurons. Microinjection of atropine, a cholinergic antagonist, into the frontal cortex suppressed the conditioned responses of 21 of 24 cortical single units. The nBM region was lesioned with kainic acid, a neurotoxin, in Experiment Three. The lesion resulted in a significant decrease in choline acetyltransferase activity in the frontal cortex ipsilateral to the nBM lesion. Only 25% of the neurons recorded in the frontal cortex on the side of the nBM lesion exhibited conditioned responses. This was significantly lower than the percentage of neurons that exhibited conditioned responses (70%) in the cortex of untreated animals. The firing rates of units in the nBM region were monitored during the cue-event paradigm in Experiment Four. Of the 38 unit recordings from the nBM region, 28 (74%) exhibited conditioned responses. The results from the four experiments together provide strong evidence for a role of the basal forebrain cholinergic system in the generation of conditioned single unit responses in the frontal cortex.