Pharmacological mechanisms in cocaine's cardiovascular effects

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Drug and Alcohol Dependence 37 (1995) 183-191

Pharmacological mechanisms in cocaine’s cardiovascular effects Charles W. Schindler*“, Srihari R. Tellaapb,Hashim K. Erzouki”, Steven R. GoldbergaTb aBehavioral Pharmacology and Genetics Section, Preclinical Pharmacology Laboratory, NIH/NIDA Division of Intramural Research, Addiction Research Center, PO Box 5180, Baltimore, IUD 21122, USA bDepartment of Pharmacology, Georgetown University School of Medicine, 3900 Reservoir Rd., Washington, DC 2&W’, USA

Received1 June 1994;accepted10August 1994

Abstract The squirrel monkey is a reliable model for the cardiovascular effects of cocaine in that it mimics the human responseto cocaine; low to moderate dosesof cocaine produce a sustained pressor effect and tachycardia. Pretreatment experiments have indicated the importance of o-1 and o-1 adrenoceptor mechanismsin mediating the pressor and tachycardiac effects of cocaine, respectively. Little support for a role of dopaminergic mechanismsin the hemodynamic effects of cocaine has been found. Toxicity to cocaine is often observedhours after its administration, pointing to a potential role of the cocaine metabolites. Studies on the direct effects of a variety of cocaine metabolites indicate that their cardiovascular effects do not necessarily mimic those produced by cocaine, and therefore thesediffering effects of the metabolites should be considered when evaluating the cardiovascular toxicity of cocaine. Further, as these metabolites are present in the body for long periods of time, these results suggesta role of the metabolites in producing toxicity long after cocaine administration. Finally, studies using both dopaminergic and calcium channel antagonists indicate that the pharmacological mechanismsinvolved in the cardiovascular effects of cocaine are not the sameas those involved in its behavioral effects. Keywork

Cocaine; Cardiovascular; Adrenoceptor; Dopamine; Behavior

1. Introduction Over the past 15 years, high levels of cocaine use have led to an increased interest in the mechanismsof action of cocaine for both its psychological and physiological effects (Johanson and Fischman, 1989). Despite the recent decreasesin the overall use of cocaine, cocainerelated emergency room visits and deaths remain at a high level. Therefore, there remains a clear need for determining the mechanismsby which cocaine produces its cardiovascular effects. The need for this understanding is not restricted only to the treatment of cocaine overdose in the emergency room. For example, since a large number of trauma victims have used cocaine (Brookoff et al., 1993), rational treatment of these patients must also take into account the potential complicating factor of the cardiovascular effects of cocaine. * Correspondingauthor. ElsevierScienceIreland Ltd. SSDI 0376-8716(94)01083-N

Further, as more and more pharmacological treatments are proposed for cocaine abuse, it is necessaryto evaluate those treatments with an eye toward the interaction of cocaine and potential treatment compounds. Without a thorough understanding of the mechanisms of action of cocaine, particularly with the cardiovascular system, evaluation of the toxicity risks associated with pharmacotherapy will be more difficult. While the need for a thorough understanding of the cardiovascular effectsof cocaine is clear, the study of the effectsof cocaine is complicated by the diverse pharmacology for this compound. For example, among the prominent actions of cocaine are both sympathomimetic and local anesthetic effects,actions which often produce opposite effects. In addition, cocaine is a potent uptake blocker not only for norepinephrine, but also for dopamine and serotonin. It is probably through this diverse pharmacology that cocaine produces such a wide spectrum of effects on the cardiovascular system.There

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et al., 1990),suggestinga role of the cocaine metabolites in producing cocaine toxicity at these later time periods. For example, Brogan et al. (1992) has recently shown a temporal association betweenrecurrent cocaine-induced coronary vasoconstriction and elevated blood concentrations of the major cocaine metabolites. Our laboratory has been studying the cardiovascular effects of drugs in animals over the past 5 years, with particular attention directed to the pharmacological mechanismsof action for cocaine. Pretreatment studies have been used to study the role of various receptor systems in the hemodynamic effects of cocaine using the squirrel monkey as a non-human primate model. These studies have focused on the conscious animal preparation, as anesthesiahas been shown to severely blunt the hemodynamic effects of cocaine (Wilkerson, 1988;Tella et al., 1990). More recently we have also begun to investigate the direct effects of the cocaine metabolites on the cardiovascular system (Erzouki et al., 1993a,b). As these studies were directed toward determining the direct cardiotoxic effects of cocaine observed at high doses, an anesthetized animal preparation was used. Finally, we have also investigated whether the behavioral and cardiovascular effects of cocaine are mediated through similar pharmacological mechanisms.

is evidence that cocaine produces an increase in resistance in the coronary and mesentericbeds (Lange et al., 1989) and there are reports of coronary and intestinal ischemias(Mizraki et al., 1988). There are also reports of cocaine-induced arrhythmias consisting of heart block (Jonssonet al., 1983),QRS widening and ventricular tachycardia (Sherief and Carpentier, 1991;TemesyArmos et al., 1992; Erzouki et al., 1993b), as well as cocaine-induced antiarrhythmic effects (Dipalma and Schultz, 1950). The diverse pharmacology of cocaine may also explain the contradictory effects that are often reported for the effects of cocaine on the cardiovascular system.For example, there have been reports of cocaine producing both increasesand decreasesin a variety of parameters such as heart rate (Catravas and Waters, 1981; Przywara and Dambach, 1989), arterial blood pressure (Teeters et al., 1963; Bedoto et al., 1988), cardiac output (Catravas and Waters, 1981; Freddrichs et al., 1990) and cardiac contractile force (O’Keefe et al., 1977; Abel et al., 1989). In addition to the above mentioned diverse effects of cocaine, the time course for cocaine toxicity is often longer than would be expected from its relatively short half-life. For example, although some patients with cocaine-associatedangina pectoris or myocardial infarction are symptomatic within minutes of drug ingestion, others do not experience symptoms for several hours (Isner et al., 1986;Amin et al., 1990), when blood concentrations of cocaine are low or undetectable. While the half-life of cocaine is relatively short, the metabolites of cocaine can be detected in urine for periods of 48 h or longer following acute administration (Ambre, 1985; Baseletand Chang, 1987;Weissand Gawin, 1988;Burke

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A variety of receptor antagonists have been used as pretreatments to study the role of adrenoceptor mechanismsin the cardiovascular effects of cocaine. In our laboratory, the conscious squirrel monkey has been used primarily for these studies and procedural details

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Fig. 1. Maximal change scoresfor mean arterial blood pressure(left panel) and heart rate (right panel) during the 30 min following cocaine (COC) (0.3 mgAtg, iv.) for squirrel monkeys pretreated with saline (SAL), phentolamine (PHEN), prazosin (PRAZ) and yohimbine (YOH). The measurementsare based on 5-min means,with the 5 min prior to the cocaine injection used as baseline. Each point is the mean * S.E.; *P < 0.05; **P < 0.01 from cocaine alone. (From Schindler et al., 1992a,Fig. I; Copyright 1992,Pergamon Press, used with permission)

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can be found in a number of published reports (Tella et al., 1990; Schindler et al., 1992a). Briefly, the squirrel monkeys are implanted with chronic iliac venous and arterial catheters during a single sterile surgery. After a two-week recovery period, the animals are seated in standard squirrel monkey restraining chairs which are placed in sound-attenuation chambers. Upon initial exposure to the restraint chair, both blood pressure and heart rate are elevated, therefore an adaptation period of two weeks is typically given prior to any drug exposure. Sessionsare usually 90 min in length. Drugs are administered no more frequently than 2 times per week to avoid the development of either tolerance or sensitization. In addition, saline is administered once per week to avoid any conditioned drug effects. Cocaine is administered 30 min into the session and pretreatment compounds are given 5-30 min prior to the cocaine injection. Blood pressure and heart rate are monitored continuously. In the squirrel monkey, cocaine in doses of 0.1-3.0 mg/kg produce a linear effect on blood pressure, with the highest dose producing increases of approximately 30-40 mm Hg (Gonzalez and Byrd, 1977; Tella et al., 1990;Schindler et al., 1992b).The effects on heart rate are more complex, with peak increases of 70-80 beats/min occurring at 0.3-1.0 mg/kg (Tella et al., 1990; Schindler et al., 1992b). At higher doses, an initial bradycardia may also be observed, an effect that appears to be related to the local anesthetic properties of cocaine (Tella et al., 1990). Fig. 1 shows the results of a study (Schindler et al., 1992a)designed to determine the effects of various CYadrenoceptor antagonists given as pretreatments to cocaine (0.3 mg/kg). The 0.3 mg/kg dose of cocaine was

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chosenfor this study as this doseproduces predominately tachycardiac effects. Previous research in our laboratory had shown that the non-specific cr-adrenoceptor antagonist phentolamine would antagonize the pressor effect of 3.0 mg/kg cocaine (Tella et al., 1990), and a clear antagonism was also observed in this study with the lower dose of cocaine (Fig. 1, left-hand panel). This antagonism was apparently due exclusively to o-1 mechanisms,as the a-1 specific antagonist prazosin produced clear blockade of the pressor effect of cocaine, while the o-2 specific antagonist yohimbine did not. The effectsof thesecompounds on the tachycardiac effect of cocaine were lessclear-cut. While all the compounds appearedto antagonize the effectsof cocaine (Fig. 1, righthand panel), all the pretreatment drugs alone also tended to produce increases in heart rate. This was particularly true for yohimbine. Therefore, the apparent antagonism of the effects of cocaine may have been a result of the elevated heart rate baseline, rather than a true pharmacological antagonism. Fig. 2 shows the results from the samestudy where @adrenoceptor antagonists were used as pretreatments. Unlike with the alpha antagonists, the predominant effects of the beta antagonists were on heart rate. The non-specific beta antagonist propranolol clearly antagonized the tachycardiac effects of cocaine, which again confirms our previous findings with a higher dose of cocaine (Tella et al., 1990). This antagonism by propranolol is probably mediated entirely though the P-1 receptor, as the 8-l specific antagonist atenolol also antagonized the tachycardiac effect of cocaine, while the P2 specific antagonist ICI 118,551 did not. Like propranolol and atenolol, the combination alpha and beta

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Fig. 2. Maximal change scoresfor mean arterial blood pressure(left panel) and heart rate (right panel) during the 30 min following cocaine (COC) (0.3 mg/kg, iv.) for squirrel monkeys pretreated with saline (SAL), propranolol (PROP), atenolol (ATEN), ICI 118,551(ICI) and labetalol (LAB). The measurementsare based on 5-min means, with the 5 min prior to the cocaine injection used as baseline. Each point is the mean f S.E.; l P < 0.05; l *P < 0.01 from cocaine alone. (From Schindler et al., 19!92a,Fig. 2; Copyright 1992,Pergamon Press, used with permission)

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antagonist labetalol antagonized tachycardiac effects of cocaine. An entirely different spectrum of effects was observed for blood pressure. Rather than an antagonism, an enhancement of the pressor effect of cocaine was observed for both the non-specific antagonist propranolol and for the 8-l specific antagonist atenolol, although the enhancement was not dose-dependentfor atenolol. Neither the b-2 specific antagonist ICI 118,551 nor labetalol affected the pressor response of cocaine. This finding was surprising in light of previous suggestions that propranolol may potentiate the pressor effect of cocaine by blocking o-2 receptors. According to this proposal, an action of cocaine at vascular p-2 receptors should produce a decrease in blood pressure which would counteract the pressureincrease produced by the action of cocaine at o-1 receptors. Propranolol, by blocking the p-2 receptors, would leave only the cocaine pressor effect on o-1 adrenoceptors. However, the fact that no potentiation was seen with the p-2 antagonist ICI 118,551 and that potentiation was also observed with the p-1 selective antagonist atenolol, suggeststhat mechanismsin addition to or other than the P-2 receptors are responsible for the potentiation observed with propranolol. Taken together, these results indicate that the pressor and tachycardiac effectsof cocaine are mediated via o-1 and p-1 adrenoceptors, respectively. In addition, these results are in good agreement with previous studies in other animal species.For example, Pitts et al. (1987) and Tella et al. (1992) in rats, and Kuhn et al. (1990) in dogs have reported that phentolamine antagonizes the pressor effects of cocaine. Likewise, Kenny et al. (1992) and Tella et al. (1992) reported that propranolol attenuates the tachycardiac effects of cocaine in dogs and rats, respectively. A number of investigators have also shown that propranolol can potentiate the effects of cocaine (e.g., Kiritsy-Roy et al., 1990;Vargas et al., 1991; Henning, 1993). Interesting, Branch and Knuepfer (1992) have recently reported that both propranolol and the 8-l antagonist metoprolol enhance the pressor and vascular resistanceeffects of cocaine. While fewer studies have addressedthe issue of receptor subtypes, these studies also are in agreement with our finding in the squirrel monkey. Recent data from our laboratory in rats has shown that prazosin will block the pressor effects of cocaine (Tella et al., 1993). In this study, however, ICI 118,551produced a potentiation of the pressor effect of cocaine in rats. Dolkart et al. (1990) has also reported that the o-1 antagonist phenoxybenzamine blocks the pressor effect of cocaine in pregnant ewes. While a-2 mechanismsdo not appear to be involved in the initial hemodynamic effects of cocaine, it is interesting to note that they do appear to be involved in the development of tachyphylaxis to repeated cocaine treatment, as both Smith et al. (1993) in rats and Jain et al. (1990) in dogs report that yohimbine pretreatment can block the development of tachyphylaxis.

Table 1 Effects of cocaine alone and in combination with haloperidol and SCH 23390on blood pressure and heart rate in the squirrel monkey

BP (30)a HR (30)” HR (60)”

0.3 Cot alone

Cot + 0.01 ha1

Cot + 0.01 SCH

20.1 f 7.3 73.1 l 5.4 89.8 f 6.3

26.5 f 7.6 53.0 f 5.5 66.1 f 7.2

31.5 f 3.0 81.8 sz 12.5 86.6 f 13.3

BP, blood pressure in mmHg; Cot, cocaine; hal, haloperidol; HR, heart rate in beats/mm; SCH, SCH 23390. “Numbers in parenthesis indicate the length of time after the cocaine injection during which the peak effect was determined. Doses are in mg/kg. Values are peak change scores f SE. for 5-min means using the 5 min prior to the cocaine injection as the baseline.

While adrenoceptor mechanisms have received the most attention in studies of the cardiovascular effects of cocaine, the diverse pharmacological effects of cocaine leaves open the possibility that other mechanisms are involved. For example, the role of dopaminergic mechanismshas received considerable attention in studies on the reinforcing effects of cocaine (Johanson and Fischman, 1989). While dopaminergic mechanisms are not usually thought to be involved in cardiovascular regulation, it has been established that both central and peripheral dopaminergic systems can regulate cardiovascular function (Nagahama et al., 1986;Nagahama et al., 1987;Chen et al., 1988).Further, there has been one report that the dopaminergic antagonist haloperidol can attenuate the cardiovascular effects of cocaine in humans (Sherer et al., 1989). Table 1 presents the results of a study by Schindler et al. (1991) where both the dopamine D2 antagonist haloperidol and the D, antagonist SCH 23390 were given as pretreatments to cocaine in conscious squirrel monkeys. Both these receptor subtypes have been identified in the periphery and have beenshown to be involved in cardiovascular regulation (Brodde, 1990). When testedagainst a dose of 0.3 mgJkg,neither antagonist attenuated the peak hemodynamic effects of cocaine. The samewas true when a higher dose of cocaine was used in testing (Schindler et al., 1991). Interestingly, inspection of the time course curves for heart rate did reveal a slight attenuation of the prolonged tachycardiac effect of cocaine (0.3 and 3.0 mg/kg) following pretreatment with 0.01 mg/kg haloperidol. This result suggeststhat dopaminergic D, mechanisms may be involved in the sustained heart rate increasesthat are observed following cocaine. However, the fact that this attenuation was minimal and that it was not dose-dependent (i.e., 0.03 mg/kg haloperidol did not attenuate the effects of cocaine) indicate that dopaminergic mechanisms play, at best, only a minor role in regulating the cardiovascular effects of cocaine. In general, these results agree with other studies investigating the role of dopaminergic mechanisms.For example, in rats Kiritsy-Roy et al. (1990) found that

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neither the D, antagonist SCH 23390 nor the D2 antagonist eticlopride could alter the hemodynamic responseto cocaine. However, eticlopride pretreatment did attenuate the release of NE by cocaine, again suggesting the possibility that D2 mechanisms may be minimally involved in the cardiovascular response of cocaine. 3. Role of metabolites In the body, cocaine is rapidly metabolized, such that very little cocaine is excreted unchanged in the urine (Jones, 1984). In fact, peak blood concentration of cocaine are often observedwithin 15min of administration and the half-life of cocaine in humans is 45-90 min (Javid et al., 1978;Javid et al., 1983).However, the toxic effects of cocaine are often not observed until hours after its administration. These clinical findings suggest that cocaine may be producing some of its toxicity through the actions of its metabolites. While previous studies had suggestedthat few, if any, of the metabolites of cocaine were pharmacologically active, more recent reports have indicated that a variety of the metabolites can exert significant effects on a variety of tissues, including the coronary (Brogan et al., 1992) and cerebral (Madden and Powers, 1990) arteries. In our laboratory, we have recently studied the effects of cocaine and the cocaine metabolites on cardiovascular function in the anesthetized rat (Erzouki et al., 1993b).This preparation was chosen so as to allow the administration of cocaine in high enough doses that its direct local anesthetic effects on the myocardium could be observed. Briefly, the rats were anesthetized with sodium pentobarbital and artificially ventilated. Both the carotid artery and jugular vein were cannulated. The artery was used for the measurement of blood pressure and the vein was used for drug administration. Arterial n BASELINE 0 E

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Fig. 3. Effects of cocaine, cocaethylene and norcocaine on QRScomplex duration in anesthetized rats. Values presented are for baseline (8), post-cocaine infusion (1.5 mg/kglmin, 0) and post NaHCO, (4 mEq/kg) administration. *P c 0.05 from baseline, +P < 0.05 from cocaine effect. (Adapted from Erzouki et al., 1993,Fig. 3; Copyright 1992,Pergamon Press, used with permission)

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blood samples were also occasionally taken for blood gas and pH analysis. Lead II of the surface EKG was routinely monitored. Following determination of baseline values, cocaine or one of its metabolites were administered as a slow infusion in one of three doses(0.15, 0.45 or 1.5 mg/kg/min). Infusions were continued until peak effects on the QRS were noted, which typically occurred 30 min after the start of the infusion. The metabolites tested were norcocaine, benzoylecgonine, ecgonine methyl ester and ecgonine. In addition, cocaethylene, a metabolite observed following the coadministration of cocaine and ethanol, was also tested. Fig. 3 shows the effects of 1.5 mg/kg/min cocaine, cocaethylene and norcocaine on the duration of the QRS. As would be expected for a local anesthetic, cocaine produced a profound increase in the QRS duration. Like cocaine, the cocaine metabolites norcocaine and cocaethylenealso demonstrated this local anesthetic effect on the QRS. Studies on the mechanism of action of cocaine on nerve conduction have shown that cocaine decreasesconduction by acting as an antagonist to sodium (Condouris, 1961). In addition, Wang (1988) and Crumb and Clarkson (1990) have shown that cocaine acts as a competitive antagonist at the sodium binding site. Thus, we tested whether replacement of sodium with sodium bicarbonate (NaHCOs) might antagonize the QRS widening seen by cocaine. These results are also shown in Fig. 3. Clearly, NaHCOJ administration was able to reversethe effectsof all three compounds on the QRS, suggestingthat this effect is mediated via sodium. However, as NaHCO, would also increase blood pH, we cannot rule out the possibility that pH change is responsible for this effect. While blood pH itself has beenshown not to affect QRS duration (Erzouki, 1991) the effect of blood pH on the cocaine-induced QRS effect was not directly assessed.None of the other metabolites tested produced any significant effects on cardiac electrophysiology. At the high doses used in the Erzouki et al. (1993b) study, the primary hemodynamic effect of cocaine was a decreasein both blood pressure and heart rate at the doseswhich also produce QRS widening. As shown in Fig. 4, cocaethyleneproduced a similar effect to cocaine on blood pressure. Unlike cocaethylene, the other cocaine metabolites produced a different spectrum of effects. In contrast to cocaine, norcocaine produced decreasesin blood pressure at a dose lower than that required to produce QRS widening. In fact, this effect of norcocaine could be completely blocked by administration of atropine, suggesting that it was due to an increase in parasympathetic function. At the higher dose, where norcocaine produced a widening of the QRS, norcocaine had a tendency to increaseblood pressure. This tendency to increase blood pressurewas even more pronounced for benzoylecgonine and ecgonine methyl ester, with increases occurring at the 0.45mg/kg/min dosefor both drugs. As with the cardiac elec-

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Fig. 4. Effects of various cocaine metabolites on mean arterial blood pressure in anesthetized rats. Drugs were infused in three different concentrations (0.15, 0.45 and 1.5 mg/kg/min). All values are changes from baseline (preinfusion). *P c 0.05 from baseline. (Adapted from Erzouki et al., 1993, Fig. 1; Copyright 1992, Pergamon Press, used with permission)

tions regarding the potential cardiovascular toxicity of cocaine. First, the fact that a number of the cocaine metabolites have potent cardiovascular effectson their own suggeststhat they may directly contribute to the toxicity of cocaine. For example, both benzolyecgonine and ecgonine methyl ester appear rapidly following cocaine administration and can be detected for long periods following its administration. Furthermore, because thesedrugs are present in the body for long periods, additional administrations of cocaine as may occur during cocaine ‘bingeing’, would be expected to exacerbate the pressoreffectsof thesecompounds, possibly resulting in serious cardiovascular complications. In addition to lengthening the time course for the cardiovascular effects of cocaine, the varying spectrum of effects produced by the metabolites may also lead to toxicity when the metabolic profile of cocaine is altered due to such factors as diseaseof the liver, age, pregnancy, genetic differences in esteraselevels, or tolerance and dependence on the drug. For example, any shift in the metabolic profile of cocaine toward norcocaine would be expected to increase the influence of the parasympathetic nervous system. Thus, it is clear that the influenceof the cocaine metabolites must also be considered when investigating the mechanismsof action for cocaine on the cardiovascular system. 4. Relationship betweenthe cardiovascular and behavioral effects of cocaine

trophysiology, ecgonine had no effect on either blood pressure or heart rate. When cocaine is administered as a smoke in ‘crack’, another group of compounds is produced as either byproducts of the smoking procedure or as metabolites. Anhydrocecgonine methyl ester (AEME) and noranhydroecgonine methyl ester (NAEME) are pyrolysis products of cocaine and anhydroecgonine ethyl ester (AEEE) is a metabolite produced when ‘crack’ cocaine and ethanol are co-administered. Both AEME and NAEME have been detected in the blood or urine of subjectswho smokecocaine. As with cocaine and its metabolites, we have recently shown (Erzouki et al., 1993a) that the pyrolysis products and their metabolites produce a different spectrum of effects from cocaine. For example, when cocaine is administered to the hindbrain of an anesthetizedrabbit via the vertebral artery, respiratory depression occurs. In contrast, AEME, NAEME and AEEE all produce respiratory stimulation. Initially, this effect would be expected to counteract that of cocaine, however, tachyphylaxis rapidly develops to the respiratory stimulation produced by the pyrolysis products, but not to the respiratory depression produced by cocaine. Therefore, with repeated administration, the respiratory depressant effect of cocaine would be expected to increase in prominence. These results have a number of important implica-

While the above discussion has focused on the cardiovascular effects of cocaine, the potent behavioral psychomotor stimulant actions of cocaine represent another class of effects which leads directly to cocaine abuse.This raisesthe question of whether the cardiovascular and behavioral effects of cocaine may share the samepharmacological processes.One approach to this question is to determine whether the samepretreatment drugs can antagonize both the behavioral effects of cocaine and its cardiovascular effects. As mentioned previously, dopaminergic processes are thought to predominate in the psychomotor stimulant effectsof cocaine, while our own studies suggest that dopamine is only minimally, if at all, involved in the cardiovascular effectsof cocaine (Schindler et al., 1991).However, most of the work implicating dopamine has been done in rodents. Our own studies have been inconclusive as to the degree of dopaminergic involvement in the behavioral effectsof cocaine in monkeys (Witkin et al., 1991), although other investigators have suggested that dopaminergic processesare important to the behavioral effects of cocaine (e.g., Spealman, 1990). Further, the one study which has looked at dopaminergic influences in the cardiovascular effects of cocaine in rodents (Kiritsy-Roy et al., 1990)failed to find any evidence of dopaminergic involvement. Thus, on the basis of this

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rather limited evidence,given that dopamine may be important to the behavioral effects of cocaine but have only limited influence on the cardiovascular effects, it would appear as though the two processesare controlled by separate pharmacological mechanisms. More recently, we have attempted to address this issuewithin a single study using calcium channel antagonists as pretreatments. As voltage sensitive calcium channels can play a crucial role in transmitter function (Middlemiss, 1985; Middlemiss and Spedding, 1985), it is reasonableto assumethat the calcium channel blockers may be capable of modifying the effects of cocaine. Further, as calcium channel blockers have clear antihypertensive effects, they would be expected to antagonize the blood pressure increasing effect of cocaine (Nahas et al., 1988). There have been reports that calcium channel blockers can modify the cardiovascular (Mutaner et al., 1988),lethal (Nahas and Trouve, 1985; Nahas et al., 1988) and hyperthermic (Rowbotham et al., 1987) effects of cocaine. With the development of calcium channel blockers which are active at central nervous systemsites (Scriabine et al., 1989), the possibility that they may also modify the behavioral effects of cocaine must also be considered. As many of the behavioral effectsof cocaine can be attributed to modification of the action of dopamine (Johanson and Fischman, 1989), it is important to note that action at calcium channels can also modulate dopamine function in the brain (Hurd and Ungerstedt, 1989; Pani et al., 1990). Further, calcium channel blockers can modify dopaminerelated behaviors (Bourson et al., 1989). Finally, there have been occasional reports that dihydropyridine calcium channel blockers can modify certain cocaineinduced effects (Pani et al., 1990; Pani et al., 1991). Mutaner et al. (1988) have also reported that nitrendipine can modify some of the subjective effects of cocaine in humans. However, other reports indicate that calcium channel blockers do not modify the behavioral effects of cocaine (Callahan and Cunningham, 1990; Mecke et al., 1991). In squirrel monkeys, we studied the effects of cocaine on cardiovascular function, schedule-controlled foodreinforced behavior and also used cocaine to maintain behavior in a drug self-administration paradigm. Three different calcium channel antagonists (nimodipine, verapamil and diltiazem) were then tested as pretreatments. All three compounds were effective as antagonists to the pressor effects of cocaine, although they did not antagonize cocaine-induced tachycardia. On schedule-controlled behavior, intermediate doses of cocaine produced increases in response rates for food while higher dosesproduced decreases.None of the calcium channel antagonists altered either of these effects of cocaine. Finally, none of the calcium channel antagonists were capable of altering cocaine self-administration. Thus, as with the results with the dopaminergic

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antagonists, these experiments appear to indicate that the cardiovascular and behavioral effects of cocaine are controlled by different pharmacological processes. 5. Conclusions To date, the evidence from our laboratory, as well as others, has clearly established a role for adrenoceptor processesin the cardiovascular effects of cocaine. It should be noted, however, that this may be an indirect effect. Adrenergic antagonists may act at peripheral adrenoceptors to block the cardiovascular effects of cocaine which might originate in the central nervous system and increase sympathetic outflow. If this is the case,the initiating effect of cocaine need not be adrenergic. Of the other receptor systems studied, none has received sufficient attention to make any firm conclusions. Clearly, there is a need for additional study. Further, almost all the studies to date have concentrated on the acute effects of cocaine. As abuse of cocaine, and therefore most casesof toxicity, involves long-term use, there is a need for studies of chronic cocaine effects on the cardiovascular system.It is entirely possible that the pharmacological influences of chronic versus acute cocaine may be different. The influence of the cocaine metabolites also deservesfurther study. Our investigations have indicated that these compounds may be important in both the acute and chronic effects of cocaine. Finally, it would appear as though the cardiovascular effects of cocaine are mediated through different pharmacological processes than are the behavioral effectsof cocaine. This finding is important in that treatment agents which may be effective against the behavioral effects of cocaine may not necessarily be expected to antagonize the cardiovascular effects. In fact, if these two systemsare mediated via different pharmacological processes,the possibility exists that an agent which is effective against the behavioral effects of cocaine could exacerbate the cardiovascular effects. Acknowledgments This paper is based on a presentation originally presented to the College on Problems of Drug Dependence, Toronto, Canada, June 1993. References Abel, F.L., Wilson, S.P., Zhao, R.R. and Fennell, W.H. (1989) Cocaine depressesthe canine myocardium. Circulatory Shock 28, 309-319. Ambre, J. (1985) The urinary excretion of cocaine metabolites in humans: a kinetic analysis of published data. J. Anal. Toxicol. 9, 241-245. Amin, M., Gabelman, G., Karpel, J. and Buttrick, P. (1990) Acute myocardial infarction and chest pain syndromesafter cocaine use. Am. J. Cardiol. 66, 1434-1437.

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