Local disinhibition of several interconnected regions in the brainstem of rats, including the dorsal midbrain, the mesencephalic locomotor region and the ventrolateral pontine reticular formation, has anticonvulsant properties in the maximal electroshock model of epilepsy. A recent anatomical study [Shehab, S., McGonigle, D., Hughes, D., Todd, A. & Redgrave, P. (2005) Eur. J. Neurosci., 22, 1431-1444.] revealed significant anatomical connections between an anticonvulsant relay region in the ventrolateral pons and reticulospinal projection neurons in the ventromedial medullary reticular formation. This pathway was shown to have both glutamatergic and GABAergic components. The purpose of the present study was to test whether local excitation or inhibition directed to the target zone of this projection in the ventral medulla would also have anticonvulsant properties. Neural excitation induced by local bilateral injections of the GABA(A) antagonist bicuculline into the ventromedial medulla caused a reliable dose-related suppression of hindlimb extension in the maximal electroshock test. The anticonvulsant effect of bicuculline was significantly greater in the terminal zone of the afferent projection from the ventral pons than that observed in adjacent tissue. Neither direct excitation following injections of N-methyl-D-aspartate nor direct inhibition by injections of the GABA agonist muscimol into the same region had reliable anticonvulsant effects. A statistically reliable association was observed between the anticonvulsant and locomotor activation effects of injections of bicuculline into the ventral medulla. No such relationship was found with bicuculline-induced disturbances of muscle tone, as reflected by the presence of postural dysfunction. Together these data establish the final functional link connecting brainstem anticonvulsant circuitry with reticulospinal systems controlling hindlimb musculature.