Cardiovascular responses to cocaine self-administration: acute and chronic tolerance.
The nature and the mechanism of tolerance to the cardiovascular responses to cocaine self-administration were studied in rats implanted with telemetric devices. The first infusion of cocaine (1 mg/kg/infusion) on day 1 of testing produced rapid and brief increases in mean arterial blood pressure and in heart rate. Subsequent infusions in the same session produced minimal effects. With chronic testing, there were gradual reductions in cardiovascular responses to the first infusion in the daily session and enhancements in the daily cocaine intake, with significant changes occurring by the fourth week of the testing. Following saline extinction testing (for 5 days), reinstatement of cocaine during week 6 led to a partial and short lasting (</=3 sessions) recovery from the chronic tolerance to the rapid cardiovascular responses to cocaine. There were significant enhancements in cardiovascular responses to post-session norepinephrine during week 2 and marked reductions during week 6 as compared to corresponding control responses. There were marked reductions in the cardiovascular responses to post-session tyramine tested during week 3. These data indicate that self-administered cocaine produces rapid and brief cardiovascular responses which undergo both within-session acute tolerance and a between-session, reversible chronic tolerance. Adrenergic adaptive mechanisms mediate the chronic tolerance. The development of chronic cardiovascular tolerance to cocaine temporally parallels that of the apparent tolerance to its reinforcing effects. Doses of cocaine that maintain self-administration behavior inhibit the norepinephrine transporter at peripheral sympathetic nerve terminals.
Tella
S R
SR
Department of Pharmacology, Georgetown University School of Medicine, Med-Dent Bldg., C405, 3900 Reservoir Road NW, Washington, DC 20007, USA. tellas@gusun.georgetown.edu
Schindler
C W
CW
Goldberg
S R
SR
D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D027981:Symporters; D013686:Telemetry; D013997:Time Factors; D014439:Tyramine / Q000494:pharmacology
D000322:Adrenergic Agonists; D002352:Carrier Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D027981:Symporters; D003042:Cocaine; D009638:Norepinephrine; D014439:Tyramine