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Rapid sensitization to the cardiovascular effects of cocaine in rats
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
50
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Fig. 1. Log dose response relationships (a, d) and time course effect of 0.1 (b, e) and 3.0 (c, f) m g / k g doses of repeated i.v. injections of cocaine on blood pressure (a-c) and heart rate (d-f) of chronically instrumented conscious rats. Open circles, filled squares and open triangles represent the responses to cocaine administered on days 1, 2 and 8, respectively. Blood pressure and heart rate changes to cocaine injections (except 1.0 m g / k g ) given on days 3, 4 and 5 (data not shown) were qualitatively and quantitatively similar to that seen on days 2 and 8. Each point is the m e a n of results obtained in 9-15 rats and brackets show S.E.s.
121 TABLE 1 Baseline blood pressure and heart rate prior to the administration of cocaine on treatment days. Values are expressed as means+ S.E. N indicates the number of animals in each group, a p < 0.05; b p < 0.01 as compared to the three groups of rats tested with 0.03, 0.1 and 3.0 mg/kg doses of cocaine Dose (mg/kg)
N
Dayl
Day2
Day3
Day4
Day5
Day8
99.9 +6.5 93.7 +3.3 111.0 +3.5 108.7 -t-4.9 102.1 +3.2
96.9 +4.2 98.5 +3.3 116.2 +2.8 112.5 +4.7 109.3 +3.7
100.9 +7.5 97.4 +3.6 115.4 +3.4 106.1 +2.1 110.9 +3.6
102.4 +6.6 104.8 +5.3 114.1 +2.4 112.4 +3.9 106.2 +3.5
295.8 +10.0 294.0 +10.4 287.3 +6.8 289.4 +8.8 304.1 + 4.0
293.8 +5.7 312.3 +9.3 297.7 +5.7 301.7 +9.7 302.7 + 8.6
301.5 +9.1 297.4 +8.7 309.4 +6.1 304.4 +7.8 311.2 + 8.7
293.7 +12.5 316.3 +7.9 307.3 +5.1 292.2 +3.6 308.4 + 7.4
Blood pressure (ram Hg)
0.03 0.1 0.3 b 1.0 a 3.0
9
102.4 99.9 +7.0 +4.3 9 100.5 98.6 +7.4 +4.9 15 120.8 115.0 +3.7 +2.9 9 111.8 111.8 +4.1 +6.8 10 102.9 98.8 +4.2 +3.4
Heart rate (beats~rain)
0.03 0.1 0.3 1.0 3.0
9
300.8 +12.9 9 305.2 +4.1 15 296.9 +8.2 9 291.7 +6.3 10 310.0 + 8.8
294.4 +9.8 310.2 +7.3 306.5 +7.0 302.2 +9.8 303.4 __.6.6
were injected with the 0.1 m g / k g dose of cocaine in their home cage on days 1-3, 5 and 8, but were injected with cocaine in an environment different from their h o m e cage on day 4. The observed peak increase in blood pressure obtained in the novel environment on day 4 (41.6 _ 3.3 m m Hg) was of a significantly (P < 0.05) greater magnitude than on day 1 (20.1 + 4.5 m m Hg), but it was not significantly different from that observed on days 2 ( 3 8 . 8 _ 3.9 m m Hg), 3 (38.2 + 3.2 m m Hg), 5 (40.9 + 3.1 m m Hg) and 8 (42.1 + 2.7 m m Hg).
4. Discussion The present data agrees with previous reports suggesting that cocaine consistently increases heart rate and blood pressure in h u m a n subjects (Lange et al., 1989) and in experimental animals (Wilkerson, 1988; Tella et al., 1990) The important finding of the present study is that the pressor effects of cocaine are markedly enhanced after a single injection. It has been previously shown that after repeated administration sensitization also occurs to cocaine's behavioral effects, such as locomotor stimulation, stereotypy and convulsions. However, there are certain differences between the development of sensitization to the behavioral and
cardiovascular actions of cocaine. First, the magnitudes of the behavioral actions of cocaine have been reported to increase progressively with repeated administrations. In the present study, however, a single exposure to cocaine e n h a n c e d the pressor response to a second injection, but no further increase in pressor response occurred with additional injections. Second, sensitization to the behavioral effects of cocaine has been reported to be dose-specific (Reith, 1986), while the present e n h a n c e m e n t of pressor effects of cocaine occurred over a wide dose range. Unlike the blood pressure response to cocaine, the heart rate response was not enhanced. However, heart rate is a particularly complex parameter that is highly susceptible to reflex effects caused by alterations in blood pressure. The increased pressor responses to repeated cocaine injections observed in the present study might have p r o d u c e d reflex effects, thereby influencing heart rate. Further, the direct depressant action of cocaine on the pacemaker function of the heart (Tella et al., 1990) also might have influenced the net o u t c o m e of cocaine's effect on heart rate. The m e c h a n i s m of sensitization to cocaine's pressor effects is not clear. The increase in pressor response to cocaine is p r o b a b l y not related to changes in pharmacokinetics. Changes in pharmacokinetics are reported to occur only after m a n y injections (Reith et al., 1987), while in the present study, the enhanced pressor response occurred after a single injection of cocaine. This rapid sensitization after only one injection suggest that the e n h a n c e d pressor response with repeated injections of cocaine was not a result of conditioning. The lack of cardiovascular effects in response to substitution of saline injections for cocaine and the continued occurrence of e n h a n c e d blood pressure responses to cocaine u p o n administration in a novel environment, further indicate that the present sensitization is not due to conditioning. Previous reports generally agree that a-adrenoceptor-mediated actions are involved in the pressor actions of cocaine (Lange et al., 1989; Tella et al., 1990), but the exact sequence of events leading to stimulation of vascular a - a d r e n o c e p t o r s is not clear. One report suggests that a central stimulant action of cocaine is the main prerequisite for s y m p a t h o m i m e t i c effects (Wilkerson, 1988), while other studies failed to obtain definitive evidence for a significant involvement of the central nervous system in cocaine's excitatory cardiovascular actions (Tella et al., 1990; W e h n e r et al., 1990). Thus, the present e n h a n c e m e n t in pressor responses to repeated injections of cocaine m a y involve either a change in the central nervous system response a n d / o r a change at the peripheral sympathetic nerve terminals, such as alteration in pre- and postsynaptic events. R a p i d sensitization to the pressor effects of cocaine, as shown in the present experiments, m a y be important
122 in the reported cardiovascular toxicity i n cocaine abusers. Pressor responses to cocaine are due to increases in total peripheral resistance secondary to its strong vasoconstrictor action (Lange et al., 1989; W e h n e r et al., 1990). I n view of recent reports revealing that a c o m m o n m e c h a n i s m of action of cocaine is involved in b o t h its pressor effects in intact a n i m a l s a n d h u m a n s (Tella et al., 1990; Lange et al., 1989) a n d its actions in causing constriction of c o r o n a r y vessels in h u m a n s (Lange et al., 1989), it is highly likely that the present sensitization to cocaine's effects o n b l o o d pressure also occurs to cocaine's effects o n c o r o n a r y circulation. If this were to be the case, the constrictor actions of cocaine o n the c o r o n a r y vascular bed w o u l d be greater after repeated a d m i n i s t r a t i o n s of cocaine. This m a y be i m p o r t a n t in c o c a i n e - i n d u c e d acute m y o c a r d i a l ischemia a n d i n f a r c t i o n in chronic cocaine abusers. A similar sensitization p h e n o m e n o n to that shown in the present experiments also m a y be involved i n the etiology of other types of cardiovascular-related toxicity thought to be p r o d u c e d b y cocaine, such as stroke a n d p u l m o n a r y hemorrhage.
Acknowledgement The authors thank S. Berger for technical assistance.
References Adams, E.H. and N.J. Kozel, 1985, Cocaine use in America: introduction and overview, in: Cocaine Use in America: Epidemiological and Clinical Perspectives, eds. N.J. Kozel and E.H. Adams (NIDA Research monograph 61, U.S. Department of Health and Human Services, Public Health Service, Alcohol Drug Abuse and Mental Health Administration, National Institute on Drug Abuse, Rockville, Maryland) p. 1. Cregler, L.L, 1989, Adverse health consequences of cocaine abuse, J. Am. Med. Assoc. 81, 27. Isner, J.M. and S.K. Chokshi, 1989, Cocaine and vasospasm, N. Engl. J. Med. 321, 1604. Lange, R.A., R.G. Cigarroa, C.W. Yancy, J.E. Willard, J.J. Popma, M.N. Sills, W. McBride, A.S. Kim and L.D. Hillis, Cocaine-induced coronary-artery vasoconstriction, N. Engl. J. Med. 321, 1557. Post, R.M. and N.R. Contel, 1983, Human and animal studies of cocaine: implications for development of behavioral pathology, in: Stimulants: Neurochemical, Behavioral, and Clinical Perspectives, ed. I. Creese (Raven Press, New York) p. 169. Reith, M.E.A., 1986, Effect of repeated administration of various doses of cocaine and WIN 35,065-2 on locomotor behavior of mice, European J. Pharmacol. 130, 65. Reith, M.E.A., M. Benuck and A. Lajtha, 1987, Cocaine disposition in the brain after continuous or intermittent treatment and locomotor stimulation in mice, J. Pharmacol. Exp. Ther. 243, 281. Tella, S.R., C.W. Schindler and S.R. Goldberg, 1990, The role of central and autonomic neural mechanisms in the cardiovascular effects of cocaine in conscious squirrel monkeys, J. Pharmacol. Exp. Ther. 252, 491. Wehner, D.M., C.A. Branch and M.M. Knuepfer, 1990, Cardiac and vascular responses to cocaine in conscious rats, Fed. Am. Soc. Exp. Biol. J. 4, A457. Wilkerson, R.D., 1988, Cardiovascular effects of cocaine in conscious dogs: importance of fully functional autonomic and central nervous systems, J. Pharmacol. Exp. Ther. 246, 466.
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
50
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Fig. 1. Log dose response relationships (a, d) and time course effect of 0.1 (b, e) and 3.0 (c, f) m g / k g doses of repeated i.v. injections of cocaine on blood pressure (a-c) and heart rate (d-f) of chronically instrumented conscious rats. Open circles, filled squares and open triangles represent the responses to cocaine administered on days 1, 2 and 8, respectively. Blood pressure and heart rate changes to cocaine injections (except 1.0 m g / k g ) given on days 3, 4 and 5 (data not shown) were qualitatively and quantitatively similar to that seen on days 2 and 8. Each point is the m e a n of results obtained in 9-15 rats and brackets show S.E.s.
121 TABLE 1 Baseline blood pressure and heart rate prior to the administration of cocaine on treatment days. Values are expressed as means+ S.E. N indicates the number of animals in each group, a p < 0.05; b p < 0.01 as compared to the three groups of rats tested with 0.03, 0.1 and 3.0 mg/kg doses of cocaine Dose (mg/kg)
N
Dayl
Day2
Day3
Day4
Day5
Day8
99.9 +6.5 93.7 +3.3 111.0 +3.5 108.7 -t-4.9 102.1 +3.2
96.9 +4.2 98.5 +3.3 116.2 +2.8 112.5 +4.7 109.3 +3.7
100.9 +7.5 97.4 +3.6 115.4 +3.4 106.1 +2.1 110.9 +3.6
102.4 +6.6 104.8 +5.3 114.1 +2.4 112.4 +3.9 106.2 +3.5
295.8 +10.0 294.0 +10.4 287.3 +6.8 289.4 +8.8 304.1 + 4.0
293.8 +5.7 312.3 +9.3 297.7 +5.7 301.7 +9.7 302.7 + 8.6
301.5 +9.1 297.4 +8.7 309.4 +6.1 304.4 +7.8 311.2 + 8.7
293.7 +12.5 316.3 +7.9 307.3 +5.1 292.2 +3.6 308.4 + 7.4
Blood pressure (ram Hg)
0.03 0.1 0.3 b 1.0 a 3.0
9
102.4 99.9 +7.0 +4.3 9 100.5 98.6 +7.4 +4.9 15 120.8 115.0 +3.7 +2.9 9 111.8 111.8 +4.1 +6.8 10 102.9 98.8 +4.2 +3.4
Heart rate (beats~rain)
0.03 0.1 0.3 1.0 3.0
9
300.8 +12.9 9 305.2 +4.1 15 296.9 +8.2 9 291.7 +6.3 10 310.0 + 8.8
294.4 +9.8 310.2 +7.3 306.5 +7.0 302.2 +9.8 303.4 __.6.6
were injected with the 0.1 m g / k g dose of cocaine in their home cage on days 1-3, 5 and 8, but were injected with cocaine in an environment different from their h o m e cage on day 4. The observed peak increase in blood pressure obtained in the novel environment on day 4 (41.6 _ 3.3 m m Hg) was of a significantly (P < 0.05) greater magnitude than on day 1 (20.1 + 4.5 m m Hg), but it was not significantly different from that observed on days 2 ( 3 8 . 8 _ 3.9 m m Hg), 3 (38.2 + 3.2 m m Hg), 5 (40.9 + 3.1 m m Hg) and 8 (42.1 + 2.7 m m Hg).
4. Discussion The present data agrees with previous reports suggesting that cocaine consistently increases heart rate and blood pressure in h u m a n subjects (Lange et al., 1989) and in experimental animals (Wilkerson, 1988; Tella et al., 1990) The important finding of the present study is that the pressor effects of cocaine are markedly enhanced after a single injection. It has been previously shown that after repeated administration sensitization also occurs to cocaine's behavioral effects, such as locomotor stimulation, stereotypy and convulsions. However, there are certain differences between the development of sensitization to the behavioral and
cardiovascular actions of cocaine. First, the magnitudes of the behavioral actions of cocaine have been reported to increase progressively with repeated administrations. In the present study, however, a single exposure to cocaine e n h a n c e d the pressor response to a second injection, but no further increase in pressor response occurred with additional injections. Second, sensitization to the behavioral effects of cocaine has been reported to be dose-specific (Reith, 1986), while the present e n h a n c e m e n t of pressor effects of cocaine occurred over a wide dose range. Unlike the blood pressure response to cocaine, the heart rate response was not enhanced. However, heart rate is a particularly complex parameter that is highly susceptible to reflex effects caused by alterations in blood pressure. The increased pressor responses to repeated cocaine injections observed in the present study might have p r o d u c e d reflex effects, thereby influencing heart rate. Further, the direct depressant action of cocaine on the pacemaker function of the heart (Tella et al., 1990) also might have influenced the net o u t c o m e of cocaine's effect on heart rate. The m e c h a n i s m of sensitization to cocaine's pressor effects is not clear. The increase in pressor response to cocaine is p r o b a b l y not related to changes in pharmacokinetics. Changes in pharmacokinetics are reported to occur only after m a n y injections (Reith et al., 1987), while in the present study, the enhanced pressor response occurred after a single injection of cocaine. This rapid sensitization after only one injection suggest that the e n h a n c e d pressor response with repeated injections of cocaine was not a result of conditioning. The lack of cardiovascular effects in response to substitution of saline injections for cocaine and the continued occurrence of e n h a n c e d blood pressure responses to cocaine u p o n administration in a novel environment, further indicate that the present sensitization is not due to conditioning. Previous reports generally agree that a-adrenoceptor-mediated actions are involved in the pressor actions of cocaine (Lange et al., 1989; Tella et al., 1990), but the exact sequence of events leading to stimulation of vascular a - a d r e n o c e p t o r s is not clear. One report suggests that a central stimulant action of cocaine is the main prerequisite for s y m p a t h o m i m e t i c effects (Wilkerson, 1988), while other studies failed to obtain definitive evidence for a significant involvement of the central nervous system in cocaine's excitatory cardiovascular actions (Tella et al., 1990; W e h n e r et al., 1990). Thus, the present e n h a n c e m e n t in pressor responses to repeated injections of cocaine m a y involve either a change in the central nervous system response a n d / o r a change at the peripheral sympathetic nerve terminals, such as alteration in pre- and postsynaptic events. R a p i d sensitization to the pressor effects of cocaine, as shown in the present experiments, m a y be important
122 in the reported cardiovascular toxicity i n cocaine abusers. Pressor responses to cocaine are due to increases in total peripheral resistance secondary to its strong vasoconstrictor action (Lange et al., 1989; W e h n e r et al., 1990). I n view of recent reports revealing that a c o m m o n m e c h a n i s m of action of cocaine is involved in b o t h its pressor effects in intact a n i m a l s a n d h u m a n s (Tella et al., 1990; Lange et al., 1989) a n d its actions in causing constriction of c o r o n a r y vessels in h u m a n s (Lange et al., 1989), it is highly likely that the present sensitization to cocaine's effects o n b l o o d pressure also occurs to cocaine's effects o n c o r o n a r y circulation. If this were to be the case, the constrictor actions of cocaine o n the c o r o n a r y vascular bed w o u l d be greater after repeated a d m i n i s t r a t i o n s of cocaine. This m a y be i m p o r t a n t in c o c a i n e - i n d u c e d acute m y o c a r d i a l ischemia a n d i n f a r c t i o n in chronic cocaine abusers. A similar sensitization p h e n o m e n o n to that shown in the present experiments also m a y be involved i n the etiology of other types of cardiovascular-related toxicity thought to be p r o d u c e d b y cocaine, such as stroke a n d p u l m o n a r y hemorrhage.
Acknowledgement The authors thank S. Berger for technical assistance.
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