Alteration of general anesthetic potency by agonists and antagonists of the polyamine binding site of the N-methyl-D-aspartate receptor.

Anesthetic potency was examined in mice after pretreatment with various putative agonists and antagonists of the polyamine site of the N-methyl-D-aspartate (NMDA) receptor. Anesthetic potency was determined for ethanol and pentobarbital by measurement of duration of loss of righting reflex, and for the volatile anesthetics, halothane and diethyl ether, by measurement of the minimum alveolar concentration (MAC). The polyamines, spermine and spermidine, increased the duration of ethanol and pentobarbital anesthesia and reduced halothane MAC, but had no effect on diethyl ether MAC. Putative antagonists of the polyamine site, ifenprodil and arcaine, also increased the anesthetic potency of ethanol, but diaminodecane, an inverse agonist, was inactive. Concurrent pretreatment with spermine or ifenprodil reduced the ability of MK-801 to increase ethanol anesthesia duration, but did not alter the ability of CGS 19755 to increase ethanol anesthesia duration. Although this study did not rule out effects of polyamines on other neurochemical systems, these results suggest that spermine and spermidines could increase anesthetic potency by acting at a site on the NMDA receptor which negatively modulates the binding of MK-801. Results of this study also suggest that the anesthetic potency of ethanol and halothane is more closely linked to the activity of brain NMDA receptors than is that of pentobarbital or diethyl ether.