The effects of activating the coeruleocortical pathway on responses of cingulate cortical cells to substance P was determined in the rat. The pathway was activated by means of small injections of glutamate, via a stereotaxically positioned cannula, directly into the locus coeruleus. Such injections greatly reduced the excitatory responses of cortical cells evoked by the iontophoretic application of substance P. Variation in the dorsal and lateral sites of injection suggested that the locus coeruleus was the important position for eliciting these effects. Depletion of cortical noradrenaline greatly reduced the ability of these injections to inhibit the substance P responses. Injections of glutamate into the locus coeruleus did not reduce cortical cell responses to acetylcholine. Parenteral administration of propranolol but not phenoxybenzamine blocked the effects of the glutamate injections on the substance P responses. These data support our previous suggestion that the central noradrenergic system may have a functional inhibitory effect on responsiveness to substance P in the cingulate cortex.