Possible novel pharmacodynamic action of cocaine: cardiovascular and behavioral evidence.
Intravenous cocaine (0.03-3 mg/kg) produced two distinct and temporally separable effects in rats. One is an initial, large, and brief increase in blood pressure (BP) and heart rate (HR) of a rapid onset (abrupt hemodynamic stimulation). A rapid, brief, and intense behavioral arousal accompanied this abrupt hemodynamic stimulation. The other effect of cocaine is a prolonged locomotor activation of a relatively slower onset. Prolonged increases in BP and HR accompanied this locomotor effect. The threshold doses of cocaine to produce abrupt hemodynamic stimulation and locomotion are 0.03 and 0.3 mg/kg, respectively. Dopamine receptor antagonists, SCH 23390 or eticlopride, at a 0.03 mg/kg dose antagonized the locomotion and the parallel prolonged increases in BP and HR, but not the initial brief behavioral arousal and abrupt hemodynamic stimulation responses to cocaine. Peripheral dopamine receptor antagonist, domperidone, altered neither behavioral nor cardiovascular effects of cocaine. Chlorisondamine (1 mg/kg), an autonomic ganglionic blocker, did not alter either the initial brief behavioral arousal or the locomotor responses to cocaine, but it prevented the cardiovascular changes that accompanied both these behavioral responses. Norepinephrine, a direct adrenergic vasoconstrictor, although produced rapid and large increase in BP, did not cause abrupt behavioral arousal or locomotor activation. Unlike cocaine, monoamine reuptake inhibitors that are selective for norepinephrine (nisoxetine, 0.1-1 mg/kg) or serotonin (fluoxetine, 0.3-3 mg/kg) produced neither brief behavioral arousal and abrupt hemodynamic stimulation nor locomotor activation. Dopamine-selective reuptake inhibitor, GBR 12,909, also did not elicit the initial brief behavioral arousal and abrupt hemodynamic stimulation. But, GBR 12,909, like cocaine, produced a prolonged locomotor effect and parallel increases in BP and HR. These effects of GBR 12,909 were prevented by SCH 23,390 and eticlopride, but not by domperidone. Similar to cocaine, cardiovascular, but not the locomotor effects of GBR 12,909 were prevented by chlorisondamine. Lidocaine (0.3-3 mg/kg), a sodium channel blocker and local anesthetic, produced neither behavioral nor physiological changes. Both cocaine (3 mg/kg) and GBR 12,909 (1 mg/kg) increased plasma norepinephrine and epinephrine concentrations. These increases were antagonized by both eticlopride and SCH 23,390. These results indicate that behavioral and cardiovascular effects of cocaine are intricately related with respect to the molecular mechanisms involved. Two pharmacodynamic actions of cocaine appear to mediate these effects. One is a dopamine-dependent while the other is a monoamine- and sodium channel-independent novel action. The former mediates cocaine's locomotor effect and the accompanying prolonged increases in BP and HR, while the latter mediates the initial brief behavioral arousal and the accompanying abrupt hemodynamic stimulation.
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Department of Pharmacology, Georgetown University School of Medicine, NW, Washington, DC 20007.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000097:blood; D002714:Chlorisondamine / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005730:Ganglionic Blockers / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D002395:Catecholamines; D018765:Dopamine Uptake Inhibitors; D005730:Ganglionic Blockers; D010879:Piperazines; C043425:vanoxerine; D003042:Cocaine; D002714:Chlorisondamine