The effect of electrical stimulation of the mesencephalic reticular formation (MRF) on the pyramidal tract (PT) response to cortical stimulation in adult rats was examined with and without alpha adrenergic blocking agents and other chemicals, applied intravenously, intraperitoneally or topically to the exposed cerebral cortex. 1. By MRF stimulation, the initial component of the PT response (D wave) was not significantly altered but the later component (I waves) was initially facilitated and subsequently inhibited. 2. Intravenously applied alpha adrenergic blocking agents, phentolamine and phenoxybenzamine consistently blocked reticulo-cortical inhibition. The reticulo-cortical facilitation was significantly reduced by phentolamine but the effect of phenoxybenazmine was not consistent on this mechanism. Neither the PT response nor the effect of MRF stimulation on it was affected by propranolol or atropine. 3. Phentolamine or phenoxybenazmine, topically applied to the cortical surface, blocked the reticulo-cortical inhibition but did not alter the reticulo-cortical facilitation. 4. A monoamine oxidase inhibitor, iproniazid (i.p.), significantly potentiated the reticulo-cortical inhibition but the effect on the reticulocortical facilitation was not statistically significant. 5. These results suggest that the reticular inhibitory effect on the motor cortical activity is mediated through an alpha adrenergic mechanism and the receptor site is distributed in the cerebral cortex.