Effects of an NMDA-receptor antagonist,MK-801, on central locomotor programming in the rabbit

Summary NMDA has been shown to disclose spinal fictive locomotor activity in various in vitro preparations. In the present work the NMDA-mediated effects of endogenously released excitatory aminoacids (EAA) on fictive locomotion in the adult rabbit preparation were assessed in vivo using systemic injections of a non competitive NMDA-antagonist, MK-801. In acute low spinal and curarized preparations, the amplitude of the spontaneous fictive locomotor activities recorded from hindlimb muscle nerves after nialamide-DOPA pretreatment was much decreased in flexor and extensor nerves after MK-801 administration (0.25 mg/kg i.v.) whereas the locomotor period increased slightly. The more potent locomotor bursts, evoked by repetitive sural nerve stimulation at 10 Hz during 10 s, were differently affected after MK-801: the main effect was a lengthening of the locomotor period and a less drastic drop in the burst amplitude. These changes in the burst period were maximal for activities evoked by A fibre group stimulation (+100%) and less when C fibres were recruited (+70%). In decerebrate curarized preparations where the locomotor sequences were evoked either by sural nerve stimulation or by stimulation of the mesencephalic locomotor region, MK-801 (0.25 mg/kg i.v.) caused the same drop in burst amplitude (by at least 50%) as in the spinal preparation but, in constrast, it reinforced rhythmic bursting: this was revealed by a clear shortening (up to-65%) of the locomotor period and by the prolongation of rhythmic bursting after stimulation. All these effects obtained in decerebrate preparations were maximal 20–30 min after MK-801 injection. Among the spinal reflexes tested by dorsal root stimulation, the mono- and disynaptic reflexes were unaffected by MK-801; the effect was limited to flexor and extensor polysynaptic reflexes which were depressed. With regard to the lumbar locomotion generators, the interpretation of the above results leads us to propose three levels of NMDA-mediated controls of locomotion by endogenously released EAA: two frequency modulations respectively responsible for the activation of the spinal locomotion generator by group A cutaneous afferents and for the strong supraspinal depression of this spinal generator; finally an amplitude modulation, achieved at a spinal, probably interneuronal level, that can amplify the out-puts of the rhythmic generated signals without modifying the pattern.