Blockade of the central generator of locomotor rhythm by noncompetitive NMDA receptor antagonists in Drosophila larvae

The noncompetitive antagonists of the vertebrate N-methyl-D-aspartate (NMDA ) receptor dizocilpine (MK 801) and phencyclidine (PCP), delivered in food, were found to induce a marked and reversible inhibition of locomotor activ ity in Drosophila melanogaster larvae. To determine the site of action of t hese antagonists, we used an in vitro preparation of the Drosophila third-i nstar larva, preserving the central nervous system and segmental nerves wit h their connections to muscle fibers of the body wall. Intracellular record ings were made from ventral muscle fibers 6 and 7 in the abdominal segments . In most larvae, long-lasting (>1 h) spontaneous rhythmic motor activities were recorded in the absence of pharmacological activation. After sectioni ng of the connections between the brain and abdominal ganglia, the rhythm d isappeared, but it could be partially restored by perfusing the muscarinic agonist oxotremorine, indicating that the activity was generated in the ven tral nerve cord. MK 801 and PCP rapidly and efficiently inhibited the locom otor rhythm in a dose-dependent manner, the rhythm being totally blocked in 2 min with doses over 0.1 mg/mL. In contrast, more hydrophilic competitive NMDA antagonists had no effect on the motor rhythm in this preparation, MK 801 did not affect neuromuscular glutamatergic transmission at similar dos es, as demonstrated by monitoring the responses elicited by electrical stim ulation of the motor nerve or pressure applied glutamate. The presence of o xotremorine did not prevent the blocking effect of MK 801. These results sh ow that MK 801 and PCP specifically inhibit centrally generated rhythmic ac tivity in Drosophila, and suggest a possible role for NMDA-like receptors i n locomotor rhythm control in the insect CNS. (C) 2001 John Wiley & Sons, I nc.