Coadministration of bicuculline and NMDA induces paraplegia in the rat

Motor neurons (MNs) of an adult rat are normally insensitive to the neurotoxic action of NMDA. Meanwhile, the experiments in non-motor neurons showed that sensitivity to NMDA can be increased by bicuculline, an antagonist at GABA(A) receptors. The aim of the present work was to examine whether bicuculline would produce such an effect in the adult MNs. In adult Wistar rats, intrathecal injection of bicuculline and NMDA individually failed to affect motor activity of the extremities. In contrast, bicuculline-NMDA combination dose-dependently impaired hindlimb functions. At the 9th day after injections of the combination, a paraplegia with persistent bilateral spastic extension developed in all animals. Light microscopic assessment showed that the development of the motor deficit is associated with pathological changes in spinal motor neurons (swelling, accumulation of the Nissl substance near nucleus, hyperchromatosis, shrinkage, and chromatolysis), mainly in the lumbar ventral horns. Additionally, distinct abnormalities were observed in the white matter of the lumbar cords. The bicuculline-NMDA combination induced a loss of spinal cord MNs while sparing the dorsal horn neurons. The effects of the combination were reversed by muscimol, a GABA(A) agonist. Thus, an inhibition of GABA(A)ergic processes can induce NMDA sensitivity in adult MNs. The present data may provide new insights into the mechanism of motor disorders in amyotrophic lateral sclerosis and other states wherein the combination of glutamatergic overstimulation and GABA(A)ergic understimulation takes place.