European Journal of Pharmacology, 194 (1991) 119-122
119
© 1991 Elsevier Science Publishers B.V. 0014-2999/91/$03.50 ADONIS 0014299991002113 EJP 20780 Short communication
Rapid sensitization to the cardiovascular effects of cocaine in rats Srihari R. T e l l a
1,2, C h a r l e s
W. S c h i n d l e r 1,3 a n d S t e v e n R. G o l d b e r g 1,3
J Behavioral Pharmacology and Genetics Laboratory, Preclinical Pharmacology Branch, National Institute on Drug Abuse Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224, U.S.A., 2 Department of Pharmacology, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20007, U.S.A. and 3 Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore, MD 21201, U.S.A.
Received 11 December 1990, accepted 18 December 1990
Effects of repeated daily administrations of cocaine on blood pressure and heart rate were studied in conscious rats. Cocaine (0.03-3.0 mg/kg i.v.) increased blood pressure and heart rate the first time it was administered (day 1) However, the magnitude and duration of the increases in blood pressure caused by cocaine (0.1-3.0 mg/kg) dramatically increased on day 2 and remained (except 1.0 mg/kg dose) at these levels through day 5. Following two drug-free days (days 6 and 7), the increase in blood pressure caused by cocaine (0.1, 0.3 and 3.0 mg/kg) on day 8 was still elevated. Unlike blood pressure, no enhancement in heart rate response to cocaine was observed. Cocaine; Blood pressure; Heart rate; Sensitization; Cardiovascular toxicity; (Rat)
1. Introduction Increased use of more effective routes of cocaine administration, such as i.v. injection and ' C r a c k ' smoking, combined with an increased purity of street cocaine have resulted in an increased number of emergency room admissions and deaths during the past decade (Adams and Kozel, 1985). A great deal of research interest has focussed on cardiovascular mechanisms of cocaine toxicity (Cregler, 1989). Accumulated evidence suggests that cocaine administration can result in acute myocardial ischemia and infarction in cocaine abusers (Isner and Chokshi, 1989), either through constriction of systemic blood vessels leading to an increase in blood pressure that in turn increases the myocardial oxygen demand, or through constriction or spasm of coronary blood vessels. The vasoconstrictor action of cocaine also has been implicated in various clinical reports of stroke and pulmonary hemorrhage in cocaine abusers (Cregler, 1989). It is now well established that repeated injections of cocaine in experimental animals can produce either sensitization or tolerance to m a n y of its behavioral actions. These phenomena have been implicated in the behavioral pathology seen in some chronic abusers of
Correspondence to: S.R. TeUa, National institute on Drug Abuse, Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224, U.S.A.
cocaine (Post and Contel, 1983). Although the effects of repeated injections of cocaine on its behavioral actions have been studied extensively, little is known about the effects of repeated injections of cocaine on the cardiovascular system. Knowledge of these effects m a y be especially important in view of the above discussed potential for cocaine to produce cardiovascular toxicity. In the present report we describe the effects of repeated cocaine injections on blood pressure and heart rate in conscious rats.
2. Materials and methods Male Sprague-Dawley rats weighing 400-500 g (Charles River Laboratories, Inc., Wilmington) were used. Polyethylene catheters were inserted into the left femoral artery and vein under halothane anesthesia for recording of blood pressure and i.v. administration of drugs respectively. Catheters were exteriorized at the back of the neck region and were protected with rodent jackets (Alice King Chatham Medical Arts, Hawthorne, CA). After surgical procedures, rats were housed individually with free access to water and food in a temperature and humidity controlled room on a 12 h fight and dark cycle. There was a postoperative recovery period of seven days. Testing with various bolus doses of cocaine (0.03, 0.1, 0.3, 1.0 or 3.0 m g / k g i.v.) was performed in home cages while blood pressure and heart rate were continuously
120
monitored. Each animal was tested with a selected dose of cocaine administered once daily for five consecutive days (days 1-5) followed by two days of no treatment (days 6 and 7) and then, one additional injection of cocaine on the eighth day. Changes in blood pressure were recorded on a Macintosh II computer using a MacLab interface and software. Heart rate was calculated from BP tracings using 3 s periods of the recording. Blood pressure and heart rate were analysed for statistical significance using two-way repeated measures analysis of variance (ANOVA) with follow-up Tukey tests for individual comparisons. Data were expressed as means + S.E.
3. Results
Cocaine doses of 0.03-3.0 m g / k g increased blood pressure and heart rate. On the first day they were administered, the effects of 0.1 (n = 9), 0.3 (n = 15), 1.0 (n = 9) and 3.0 (n = 10) m g / k g doses of cocaine on blood pressure were of a small magnitude (fig. la). When these same doses of cocaine were again administered on day 2, their peak pressor effects increased dramatically (P < 0.05) and increases in pressure lasted longer (P < 0.05) than on day 1 (fig. l b and c). N o further increase in pressor response to cocaine (except 1.0 m g / k g dose) was observed over the next three successive days of treatment (up to day 5), or on day 8, after two drug-free days. The enhancement in pressor response to 1.0 m g / k g dose of cocaine on days 3
a
60
through 8, unlike on day 2, did not reach statistical significance. N o enhancement of pressor response was seen with 0.03 (n = 9) m g / k g cocaine. The log dose-response curves for cocaine's effects on blood pressure obtained on days 2, 3, 4, 5 and 8 were steep and showed a leftward shift with an increased maximal response compared to the dose-response curve obtained on day 1. Unlike the blood pressure, no enhancement in the magnitude of the tachycardiac response to cocaine was seen during the test days (fig. ld). However, the durations of the increases in heart rate produced by 3.0 m g / k g cocaine on days 2 through 8 were significantly (P < 0.05) longer than on day 1 (fig. lf). The mean baseline blood pressure and heart rate of groups of rats over the six test days are shown in table 1. Baseline heart rates were not significantly different during the test days. Baseline blood pressures of two groups of rats treated with 0.3 (P < 0.01) and 1.0 (P < 0.05) m g / k g doses during all the test days were significantly greater than the remaining groups of rats treated with 0.03, 0.1 and 3.0 m g / k g doses of cocaine. However, the enhancement of pressor response to cocaine does not seem to be related to baseline blood pressure as this enhancement was seen over a wide dose range (0.1-3.0 m g / k g ) . To study the potential role of conditioning in the enhanced cardiovascular responses to cocaine, we studied the effect of a saline injection on day 9 in a group of nine rats who had been tested with the 0.1 m g / k g dose of cocaine on days 1-5 and on day 8; this placebo injection produced no change in blood pressure or heart rate. We also tested a group of nine rats, who
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119
© 1991 Elsevier Science Publishers B.V. 0014-2999/91/$03.50 ADONIS 0014299991002113 EJP 20780 Short communication
Rapid sensitization to the cardiovascular effects of cocaine in rats Srihari R. T e l l a
1,2, C h a r l e s
W. S c h i n d l e r 1,3 a n d S t e v e n R. G o l d b e r g 1,3
J Behavioral Pharmacology and Genetics Laboratory, Preclinical Pharmacology Branch, National Institute on Drug Abuse Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224, U.S.A., 2 Department of Pharmacology, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20007, U.S.A. and 3 Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore, MD 21201, U.S.A.
Received 11 December 1990, accepted 18 December 1990
Effects of repeated daily administrations of cocaine on blood pressure and heart rate were studied in conscious rats. Cocaine (0.03-3.0 mg/kg i.v.) increased blood pressure and heart rate the first time it was administered (day 1) However, the magnitude and duration of the increases in blood pressure caused by cocaine (0.1-3.0 mg/kg) dramatically increased on day 2 and remained (except 1.0 mg/kg dose) at these levels through day 5. Following two drug-free days (days 6 and 7), the increase in blood pressure caused by cocaine (0.1, 0.3 and 3.0 mg/kg) on day 8 was still elevated. Unlike blood pressure, no enhancement in heart rate response to cocaine was observed. Cocaine; Blood pressure; Heart rate; Sensitization; Cardiovascular toxicity; (Rat)
1. Introduction Increased use of more effective routes of cocaine administration, such as i.v. injection and ' C r a c k ' smoking, combined with an increased purity of street cocaine have resulted in an increased number of emergency room admissions and deaths during the past decade (Adams and Kozel, 1985). A great deal of research interest has focussed on cardiovascular mechanisms of cocaine toxicity (Cregler, 1989). Accumulated evidence suggests that cocaine administration can result in acute myocardial ischemia and infarction in cocaine abusers (Isner and Chokshi, 1989), either through constriction of systemic blood vessels leading to an increase in blood pressure that in turn increases the myocardial oxygen demand, or through constriction or spasm of coronary blood vessels. The vasoconstrictor action of cocaine also has been implicated in various clinical reports of stroke and pulmonary hemorrhage in cocaine abusers (Cregler, 1989). It is now well established that repeated injections of cocaine in experimental animals can produce either sensitization or tolerance to m a n y of its behavioral actions. These phenomena have been implicated in the behavioral pathology seen in some chronic abusers of
Correspondence to: S.R. TeUa, National institute on Drug Abuse, Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224, U.S.A.
cocaine (Post and Contel, 1983). Although the effects of repeated injections of cocaine on its behavioral actions have been studied extensively, little is known about the effects of repeated injections of cocaine on the cardiovascular system. Knowledge of these effects m a y be especially important in view of the above discussed potential for cocaine to produce cardiovascular toxicity. In the present report we describe the effects of repeated cocaine injections on blood pressure and heart rate in conscious rats.
2. Materials and methods Male Sprague-Dawley rats weighing 400-500 g (Charles River Laboratories, Inc., Wilmington) were used. Polyethylene catheters were inserted into the left femoral artery and vein under halothane anesthesia for recording of blood pressure and i.v. administration of drugs respectively. Catheters were exteriorized at the back of the neck region and were protected with rodent jackets (Alice King Chatham Medical Arts, Hawthorne, CA). After surgical procedures, rats were housed individually with free access to water and food in a temperature and humidity controlled room on a 12 h fight and dark cycle. There was a postoperative recovery period of seven days. Testing with various bolus doses of cocaine (0.03, 0.1, 0.3, 1.0 or 3.0 m g / k g i.v.) was performed in home cages while blood pressure and heart rate were continuously
120
monitored. Each animal was tested with a selected dose of cocaine administered once daily for five consecutive days (days 1-5) followed by two days of no treatment (days 6 and 7) and then, one additional injection of cocaine on the eighth day. Changes in blood pressure were recorded on a Macintosh II computer using a MacLab interface and software. Heart rate was calculated from BP tracings using 3 s periods of the recording. Blood pressure and heart rate were analysed for statistical significance using two-way repeated measures analysis of variance (ANOVA) with follow-up Tukey tests for individual comparisons. Data were expressed as means + S.E.
3. Results
Cocaine doses of 0.03-3.0 m g / k g increased blood pressure and heart rate. On the first day they were administered, the effects of 0.1 (n = 9), 0.3 (n = 15), 1.0 (n = 9) and 3.0 (n = 10) m g / k g doses of cocaine on blood pressure were of a small magnitude (fig. la). When these same doses of cocaine were again administered on day 2, their peak pressor effects increased dramatically (P < 0.05) and increases in pressure lasted longer (P < 0.05) than on day 1 (fig. l b and c). N o further increase in pressor response to cocaine (except 1.0 m g / k g dose) was observed over the next three successive days of treatment (up to day 5), or on day 8, after two drug-free days. The enhancement in pressor response to 1.0 m g / k g dose of cocaine on days 3
a
60
through 8, unlike on day 2, did not reach statistical significance. N o enhancement of pressor response was seen with 0.03 (n = 9) m g / k g cocaine. The log dose-response curves for cocaine's effects on blood pressure obtained on days 2, 3, 4, 5 and 8 were steep and showed a leftward shift with an increased maximal response compared to the dose-response curve obtained on day 1. Unlike the blood pressure, no enhancement in the magnitude of the tachycardiac response to cocaine was seen during the test days (fig. ld). However, the durations of the increases in heart rate produced by 3.0 m g / k g cocaine on days 2 through 8 were significantly (P < 0.05) longer than on day 1 (fig. lf). The mean baseline blood pressure and heart rate of groups of rats over the six test days are shown in table 1. Baseline heart rates were not significantly different during the test days. Baseline blood pressures of two groups of rats treated with 0.3 (P < 0.01) and 1.0 (P < 0.05) m g / k g doses during all the test days were significantly greater than the remaining groups of rats treated with 0.03, 0.1 and 3.0 m g / k g doses of cocaine. However, the enhancement of pressor response to cocaine does not seem to be related to baseline blood pressure as this enhancement was seen over a wide dose range (0.1-3.0 m g / k g ) . To study the potential role of conditioning in the enhanced cardiovascular responses to cocaine, we studied the effect of a saline injection on day 9 in a group of nine rats who had been tested with the 0.1 m g / k g dose of cocaine on days 1-5 and on day 8; this placebo injection produced no change in blood pressure or heart rate. We also tested a group of nine rats, who
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