Antagonism of the toxicity of cocaine by MK-801: differential effects in spontaneously hypertensive and Wistar-Kyoto rats.

A putative role for endogenous excitatory amino acid systems in the mediation of the cardiovascular and toxic responses to acute administration of cocaine, was examined in spontaneously hypertensive and normal Wistar-Kyoto rats. Conscious, restrained, male hypertensive and normal rats (12 weeks of age) received either the non-competitive excitatory amino acid receptor antagonist, MK-801 (0.01-10 mg/kg, i.v.) or vehicle, 30 min prior to initiation of infusion of cocaine hydrochloride (1.25 mg/kg min, i.v.). Administration of MK-801 produced increases in mean blood pressure and heart rate in both hypertensive and normal rats. Resting rectal temperature was reduced by MK-801 only at the largest dose tested (10 mg/kg). Infusion of cocaine caused convulsions and death at doses of 27.8 +/- 2.3 and 48.2 +/- 5.7 mg/kg, respectively in the normals, and 21.2 +/- 2.5 (P < 0.05) and 31.1 +/- 3.4 (P < 0.05) in the hypertensive rats. Pretreatment with MK-801 abolished the enhanced sensitivity of the hypertensive rats to the toxicity of cocaine. The doses of cocaine required to cause death were significantly increased, in the hypertensive rats at doses > or = 0.05 mg/kg, an effect which was not evident, at any dose, in the normals. The maximally effective dose of MK-801 (0.5 mg/kg) increased the dose of cocaine required to cause lethality by 272% (P < 0.05) in the hypertensive rats; the increase produced by MK-801 in the normals (163%) was not significant. Cocaine-induced convulsions were abolished in both hypertensive and control rats with doses of MK-801 > 0.1 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)