ATTENUATION OF THE CARDIAC EFFECTS OF COCAINE BY DIZOCILPINE

Cocaine abuse causes autonomic and cardiovascular effects that may be life threatening. Attenuation of cocaine-induced seizures has been produced by the noncompetitive antagonist of the N-methyl-D-aspartate receptor channel complex, dizocilpine. The purpose of the present study was, first, to determine effects of dizocilpine on the incidence of pacing-induced ventricular arrhythmias and, second, to evaluate the effects of dizocilpine on cocaine-induced depression of sympathetic efferent activity to the heart. Adult dogs were anesthetized and instrumented for blood pressure and an electrocardiogram. After vagotomy and thoracotomy, electrodes and strain gauges were sutured onto the right atrium and ventricle. A left thoracic sympathetic efferent nerve was isolated and stimulated for analysis of the innervation pattern. Arrhythmias were induced with programmed electrical stimulation of the heart before and during left cardiac sympathetic efferent nerve stimulation. The control incidence of induced arrhythmias was only 2%, which increased to 21% during left sympathetic stimulation. Cocaine (2 mg/kg iv) significantly increased these to 11 and 42%, respectively. Dizocilpine (0.5 mg/kg iv) reduced the incidence of induced ventricular arrhythmias to 2% with cocaine (P < 0.05) and to 19% with cocaine and left sympathetic stimulation (P < 0.01). One or two sympathetic efferent cardiac nerves were stimulated to evaluate innervation patterns. These nerves were severed and prepared for recording multifiber efferent neurograms. Nerve traffic was analyzed by counting positive spikes for 15 s. Control activities were normalized at 100%. Within 6 min, cocaine (2 mg/kg iv) reduced the sympathetic efferent activity to 83 +/- 4% of control (n = 14 nerves). After at least 60 min of recovery, dizocilpine (0.5 mg/kg iv) was given. A second administration of cocaine reduced the sympathetic efferent activity to only 94 +/- 3% of control. This is significantly (P < 0.02) less than the initial depression. In another group of dogs pretreatment with dizocilpine before cocaine prevented the cocaine-induced depression in sympathetic efferent activity to the heart (n = 16 nerves). Thus the proarrhythmic effects of cocaine and cocaine-induced sympathetic efferent depression to the heart are attenuated by the dizocilpine.