URETHANE ANESTHESIA REVERSES THE PROTECTIVE EFFECT OF NONCOMPETITIVE NMDA RECEPTOR ANTAGONISTS AGAINST COCAINE INTOXICATION

The present experiments examined whether pretreatment with the noncomp etitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 and d extrorphan, could antagonize cocaine-induced convulsions and lethality in conscious Sprague-Dawley (SD) rats and whether urethane anesthesia alters the observed interactions. Conscious, restrained male SD rats received continuous i.v. infusions of cocaine hydrochloride (1.25 mg/k g.min) until convulsions and death occurred. Cocaine doses of 21.2+/-1 .8 and 29.5+/-2.5 mg/kg caused convulsions and death, respectively, in saline treated rats (n=8). Convulsions were absent in MK-801 (1 mg/kg , i.v.; n=8) pretreated rats; the lethal cocaine dose was 44.0+/-2.7 m g/kg (p < 0.05). In contrast, urethane anesthesia (1.2 g/kg, i.p.) dec reased The dose of cocaine required to cause toxicity, compared to tha t in saline controls (24.8+/-0.8 mg/kg, n=13), in MK-801 (2.0+/-0.3, n =7; p < 0.01) and in dextrorphan (25 mg/kg, i.v.; 13.1+/-1.4, n=6; p < 0.01) pretreated rats. Presser responses with little change in heart rate were evident during cocaine infusion in vehicle pretreated rats. Bradycardic responses were noted to cocaine in groups following NMDA r eceptor blockade. Reversal of the presser response to cocaine was note d in MK-801 pretreated animals, while dextrorphan pretreatment moderat ed cocaine-induced increases in blood pressure. Ventilatory support pr otected against cocaine lethality in urethane anesthetized rats, indic ating that respiratory failure is the proximate cause of death with co caine infusion. However, artificially ventilated rats, pretreated with MK-801, were more sensitive (lethal cocaine dose, 76.6+/-8.0 mg/kg, n =5) than vehicle pretreated rats (129.4+/-15.8 mg/kg, n=6) indicating that MK-801 may increase both the respiratory and the cardiac toxicity of cocaine in urethane anesthetized rats. Interactions between NMDA r eceptors and cocaine are modified by urethane anesthesia.