INTERFERING WITH GLUTAMATERGIC NEUROTRANSMISSION BY MEANS OF NMDA ANTAGONIST ADMINISTRATION DISCLOSES THE LOCOMOTOR STIMULATORY POTENTIAL OF OTHER TRANSMITTER SYSTEMS

In the present paper it is shown that when either of the noncompetitive NMDA antagonists MK-801 or ketamine are combined with the α-adrenergic agonist clonidine, a pronounced stimulation of locomotion is produced in monoamine-depleted mice. Likewise, when a subthreshold dose of MK-801 is combined with the muscarinic antagonist atropine, a forceful synergism with regard to locomotor activity in monoamine-depleted mice is observed. Furthermore, the present study shows that also in monoamine-depleted rats MK-801, as well as the competitive NMDA antagonist AP-5 (DL-2-amino-5-phosphonovaleric acid), interact synergistically with clonidine to enhance locomotor activity. Taken together, our findings suggest that central glutamatergic systems exert a powerful inhibitory influence on locomotion. Interfering with this inhibitory force by administration of an NMDA antagonist promotes locomotion and discloses the activational potential of other transmitter systems. The results are discussed in relation to 1) the pathophysiology of schizophrenia, with emphasis on the glutamate hypothesis of schizophrenia, and 2) implications for the treatment of Parkinson's disease. © 1990.