Urethane anesthesia reverses the protective effect of noncompetitive NMDA receptor antagonists against cocaine intoxication.

The present experiments examined whether pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 and dextrorphan, 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/kg.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 mg/kg (p < 0.05). In contrast, urethane anesthesia (1.2 g/kg, i.p.) decreased the dose of cocaine required to cause toxicity, compared to that 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 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. Pressor responses with little change in heart rate were evident during cocaine infusion in vehicle pretreated rats. Bradycardiac responses were noted to cocaine in groups following NMDA receptor blockade. Reversal of the pressor response to cocaine was noted in MK-801 pretreated animals, while dextrorphan pretreatment moderated cocaine-induced increases in blood pressure. Ventilatory support protected against cocaine lethality in urethane anesthetized rats, indicating that respiratory failure is the proximate cause of death with cocaine 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 receptors and cocaine are modified by urethane anesthesia.