Effect of cocaine on vagal tone: a common factors approach

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Drug and Alcohol Dependence 37 (1995) 211-216

Effect of cocaine on vagal tone: a common factors approach David B. Newlin NIDA Intramural

Research Program, Baltimore, MD, USA

Received 19 July 1994; accepted I5 October 1994

Abstract This paper discussesa distinct cardiovascular pattern that is common to a wide variety of abusedsubstances.The pattern consists of tachycardia that appears mediated by withdrawal of vagal inhibition, as indicated by decreasesin cardiac vagal tone. This decreasein vagal tone was particularly robust with i.v. cocaine given to experiencedcocaine abusersin a residential researchsetting. Following 40 mg i.v. cocaine, heart rate increased by approximately 30 beats/min at the sametime that vagal tone decreasedby approximately 2 log units. The theoretical significance of thesefindings is basedon evidencethat the results reflect a common factor among many abused drugs, but not the few aversive drugs that have been studied in this paradigm. Keywords:

Cocaine; Parasympathetic; Sympathetic; Common factors; Abuse liability; Tachycardia; Vagal tone; Cardiovascular

1. Introduction It was less than a decade ago that the specific autonomic mechanism of the cardiovascular effects of cocaine in humans was thought to be relatively well understood (Ritchie and Greene, 1991). This is no longer the case. The complexity of the autonomic nervous system and its central (brain) control has made it difficult to isolate precise mechanisms.Even the deceptively simple question of whether the effects of cocaine on the heart are centrally or peripherally controlled has generated intense controversy (see other reports in this issue). The purpose of this paper is to direct attention toward parasympathetic as opposed to sympathetic mechanismsof the cardiac effects produced by cocaine in human volunteers, and to place this program of research within a broader theoretical and empirical context. This research began with the simple question of whether drugs of abuse administered acutely to human volunteers would affect vagal tone. The researchwas facilitated by development of a non-invasive measure of respiratory sinus arrhythmia based on time seriesanalysis of the electrocardiogram (ECG) (Porges, 1985).This measure, vagal tone index (v), is thought to reflect

rather purely the inhibitory effects of efferent outflow to the heart from the vagus nerve (Porges, 1986). V is exquisitely sensitive to vagal blockade with atropine (Yongue et al., 1982; Dellinger et al., 1987), and has been shown to respond to various psychophysiological stimuli such as cognitive workload and sustained attention (Suesset al., 1994).This validation and application work allowed us to measure V in human volunteers receiving drugs acutely, and to make relatively strong inferences concerning parasympathetic (i.e., vagallymediated) effects of these compounds. The obvious alternative to measuring changesin V in responseto abused drugs is to produce parasympathetic blockade prior to administering the drug of abuse, such as cocaine. If atropine blocked the effect of, for example, cocaine on heart rate and other related cardiovascular parametersbut placebo did not, then this would be strong evidence that the effect of cocaine was parasympathetically mediated. This is a classic drug-drug interaction study. However, it would not be possible to perform this study in humans. In humans, vagal blockade produces large increasesin resting heart rate. (Dellinger et al., 1987). In many cases,heart rate will almost double in response to pretreatment with an effective vagal blocker (Berne and Levy, 1977).Therefore, resting

0376-8716/95RO9.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0376-8716(94)01086-Z

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D. B. Newlin / Drug and Alcohol Dependence 37 (1995) 211-216

heart rate would be too high in humans to safely allow the administration of a second drug, such as cocaine, that might increaseheart rate further. Moreover, the extreme shift in baseline heart rate would be so great that the effect of cocaine could be changed radically from that at resting levels. This would make drawing inferences from the results of such a study impossible. Finally, one would expect ceiling effects in heart rate that might prevent further tachycardia from cocaine after vagal blockade. This would appear to confirm that vagal blockage prevented tachycardia from cocaine when the effect was purely artifactual (i.e., due to ceiling effectsin the cardiovascular system). The result of these considerations is that the most effective way to answer the question of whether there are parasympathetic components to the cardiovascular effect of cocaine in humans is with a concomitant measure such as V. One might argue that an animal model would provide a more definitive answer. To some extent this is true. The problem with this approach is the ultimate question of whether the animal model is fully applicable to humans for that particular effect. This generalizability would be tested in humans in the end, anyway. Moreover, it might be necessaryto test the same effect in many different speciesto determine the generalizability between animals, when the real question involves human pharmacology. 2. Effect of i.v. cocaine on vagal tone There is evidencefor a cardiovascular pattern that appearsto be a common factor among drugs of abuse. The evidencefor this common factor has been obtained very recently. Moreover, it has beenstudied almost exclusively in humans, some of whom were established drug abusersand someof whom were relatively naive to illicit drugs (with tests of acute nicotine and alcohol). Researchon this common factor has beenmade possible by the development, noted above, of a non-invasive measure of parasympathetic influences on the heart (Porges, 1986), or vagal tone index (v). Although by no means a routine psychophysiological measure, V has been relatively well validated as a measure of cardiac vagal tone, or the gating of vagal nerve inhibition of chronotropic function of the heart by respiratory afferent reflexes. Since V is derived from time series analysis of the ECG (Porges, 1985),it becamepossible to measure I/in any laboratory study in which individuals were administered abused substances under intense medical supervision following strict screening procedures. One implication of these medical considerations is that individuals with virtually any cardiovascular problem or ECG abnormality were excluded from participation. Therefore, the vagal tone results are generalizable only to individuals with normal cardiovascular parameters,

and may not reflect those of the many substanceabusing individuals with minor or major cardiovascular abnormalities. It is here that an animal model would be particularly useful. For example, it would be possible in rodents or primates to determine whether animals with experimenter-induced cardiac arrhythmias would demonstrate vagally-mediated responsesto cocaine and other drugs that differ from animals without such abnormalities. Most of the research concerning the cardiovascular effects of cocaine has focused on sympathetic pathways (seeother papers in this issue). In humans, it has been customary to record heart rate and systolic and diastolic blood pressuresin substanceabusers as they receive cocaine in the laboratory setting (Fischman et al., 1976). Moreover, clear and consistent evidence that cocaine increasesheart rate and blood pressure has been taken as evidence of the ‘sympathomimetic’ effects of cocaine (Jaffe, 1991;Ritchie and Greene, 1991). However, both heart rate and blood pressure are derivative measures (Berne and Levy, 1977). Most important to this discussion is the fact that tachycardia can be due either to increased sympathetic activation through P-adrenergic receptors, or to withdrawal of parasympathetic inhibition of the heart. Becausevagal nerve activation inhibits heart rate in a tonic manner, any reduction in vagal tone will allow heart rate to rise. This is particularly apparent in humans, where tonic vagal inhibition is profound, and where tonic fl-adrenergic activation is limited (Berne and Levy, 1977). These characteristics could be associatedwith important speciesdifferences in cardiovascular architecture. Although not a focus of this particular investigation, blood pressureis also a derivative measure. In terms of neural influences, a-adrenergic activation leads to large pressor responsesinvolving both systolic and diastolic blood pressures. /3-Adrenergic activation produces greater increases in systolic than diastolic blood pressure. Therefore, as in the case with tachycardia, a pressor response does not necessarily implicate activation of P-adrenergic receptors. As a working hypothesis, we propose the notion that the supposedly ‘sympathomimetic’ effect of cocaine in humans is not /3-adrenergicat all; rather, the observed tachycardia is due to withdrawal of vagal inhibition, and the mechanismof the pressor responseto cocaine in humans is ar-adrenergicactivation. We performed a simple test of the first half of this hypothesis. We predicted that i.v. cocaine at 20-mg and 40mg dosageswould decreaseV in a dose dependent manner compared to iv. placebo. The subjects were 14 men with extensive i.v. cocaine experience, but who were not dependent on any drug other than nicotine (from tobacco) at the time of testing. They were housed on a residential researchunit at the Addiction Research Center, and had no accessto drugs other than nicotine; this was

D. B. Newlin / Drug and Alcohol

confirmed by urine toxicology. These volunteers were not in treatment, at their request. The protocol was reviewed and approved by the Institutional Review Board. Subjects were paid for participation. The study reported here was part of a larger study (London et al., 1990) of regional glucose utilization (using positron emission tomography; PET), although PET testing was subsequent to the psychophysiological testing reported here. All subjects were given a single-blind placebo (i.v. saline injection) in the first laboratory session.This ensured that they were familiar with the laboratory procedure, and that habituation to the recording surface electrodes(including EEG) had taken place prior to cocaine infusions (Newlin and Pretorius, 1991). The design of the experiment involved three doubleblind sessionsin the laboratory: (i) placebo; (ii) 20 mg i.v. cocaine; and (iii) 40 mg i.v. cocaine. The injections were given by a physician with a 10-sinjection interval. These sessions were in random order, with the constraint that the 20-mg sessionalways camebefore the 40mg session.Therefore, placebo could occur in the first, second or last session. The results confirmed our prediction. Fig. 1 illustrates increasesin heart rate and decreasesin V approximately 10 min after the injection of cocaine or placebo. This was the maximal effect in terms of both measures. In fact, the heart rate and vagal tone measuresappeared to be mirror opposites, a result that implicates the decrease in V as a mechanism of the tachycardia. The relatively long latency to maximal response (10 min) has been observed previously (Fischman et al., 1976) in humans. Fig. 2 illustrates the effect of 40 mg cocaine in a subject who demonstrated a particularly large response. In this subject, there was a profound suppression of heart rate variability in the respiratory band - the function that V quantifies - following cocaine.

Vagal Tone

Heart Rate

(2 5) -

sdne

coc20

cocno

Fig. I. Mean increasesin heart rate (beatdmin) from pre-drug baseline and mean decreasein vagal tone index (V, in log units). These are changesat the interval of maximal response,approx. 10 min after i.v. injection of saline, cocaine (20 mg) or cocaine (40 mg).

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Fig. 2. Continuous tracing of heart rate over 120-s(Zmin) trme mtervals for one subject who showed a particularly robust responseto i.v. cocaine.The lower tracing is during a resting baseline before injection, and the upper tracing is after 40 mg cocaine. Note that in this subject, cocaine produced profound decreasesin heart rate variability in the respiratory band (i.e., vagal tone index), as well as an approximate doubling of heart rate.

Theseresults indicate that cocaine produces tachycardia that is mediated primarily by withdrawal of cardiac vagal tone. As parasympathetic inhibitory influences on the heart are reduced, heart rate increases.In some subjects (see Fig. 2), these changes can be profound. 3. Other abuseddrugs and vagal tone We have reported similar results, increased heart rate due to withdrawal of vagal tone, in studies with a number of different drugs of abuse.Thesedrugs have included oral alcohol (Newlin et al., 1990), i.v. nicotine, smoked marijuana (Newlin et al., 1991), i.v. morphine and i.m. morphine (Pretorius et al., 1990), oral hydromorphone, oral pentobarbital, and oral methylphenidate. The tachycardia and concomitant decreasesin V were pronounced with cocaine (above), nicotine and marijuana; they were moderate with alcohol, methylphenidate and pentobarbital; and they were more subtle, but statistically significant, with the opiates. We have found that oral d-amphetamine failed to increase heart rate or decreasevagal tone. This might appear to be an important exception to the apparent rule that abused substancesall seemto show the distinct cardiovascular pattern found with cocaine. This exception would appear to be particularly important because it is clear that d-amphetamine has strong dopaminergic effects. However, two piecesof evidence suggestthat this ap-

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parent failure to find the same cardiovascular pattern with d-amphetamine is artifactual. First, we found that methylphenidate, a similar amphetamine-like compound with potent dopaminergic effects does, in fact, increase heart rate at the same time that it decreases vagal tone. Second, there are old studies (Martin et al., 1971)showing that d-amphetamine elicits a strong baroreceptor reflex that may obscure the cardiovascular pattern that we report with cocaine. Evidence for this baroreceptor response was from negative correlations between heart rate and blood pressure for d-amphetamine, indicating that reflexive responsesto the pressor effectsof d-amphetamine depressheart rate at the same time that the drug would otherwise produce tachycardia. Positive correlations were found (Martin et al., 1971) between heart rate and blood pressure for methylphenidate, indicating that the baroreceptor response was not elicited by this drug. Therefore, it appears that d-amphetamine is an exception to the rule for artifactual reasons. Methylphenidate is a drug with dopaminergic effects whose cardiovascular profile is unobscured by the baroreceptor response. 4. Aversive drugs

Before concluding that decreasedV is a common factor among abused drugs, it is necessary to consider drugs that are subjectively aversive. We reasoned that if decreasedV was, indeed, related to the abuse potential of these drugs, then it should not be decreasedby aversive drugs. We were able to study the effectsof naloxone challengein opioid-dependent individuals to test this hypothesis. In a standard study of naloxone-precipitated withdrawal in 19 opioid dependent men and women, we (Newlin et al., 1992)found that this challenge led to an increasein heart rate, but no change in V. We tested the limits of this finding by selecting those individuals-that showed the greatest tachycardia to naloxone, and this subgroup failed to show any significant change in V. We concluded that the tachycardia from naloxone-precipitated withdrawal was sympathetic (P-adrenergic) rather than vagal in origin (Newlin et al., 1992). Preliminary studies with mCPP, which was dysphoragenic in the four subjectsthat we studied, also failed to change V(Newlin et al., 1992).Finally, in a very preliminary investigation of withdrawal from alprazolam precipitated by flumazenil injection, we found that alprazolam increased heart rate and decreasedV. More importantly, flumazenil alone had no effect on V in the three subjects that were tested, and it produced tachycardia (unaccompanied by changes in V) only when precededby alprazolam. Thesedata, though preliminary in the caseof mCPP and flumazenil, seemto rule out at least some aversive drugs showing the same effects on V as abused drugs.

5. Common factors

As noted above, this program of research began with a simple pharmacological question: What is the effect of abused drugs on V? It soon changed to the question of whether all abused drugs demonstrate a common factor of reducing vagal tone; and then whether this pattern was unique to abused drugs, or would be found also with subjectively aversive drugs (such as naloxone precipitated withdrawal in opioid dependent individuals). As reported above, our preliminary research supports the contention that abuseddrugs increaseheart rate at the sametime that they decrease V, while drugs that are not abused do not show this pattern. As the program of researchdeveloped, we becameinterestedin the theoretical question of how one interprets a common factor in the substanceabuse field. We might define a common factor as a pattern or effect which characterizes a wide range of abused drugs. Moreover, this factor is not common to aversive drugs, or those drugs that are subjectively neutral and are not abused in our society. Over the last few decades, several common factors have been identified. Many of these common factors, such as drug self-administration in an instrumental paradigm, have been viewed as breakthroughs in the drug abuse field. Their importance grew as evidence developedthat thesefactors were common to a wide variety of abuseddrugs. Moreover, someof thesecommon factors, such as locomotor activation (Wise and Bozarth, 1987), drug self-administration, conditioned place preference, and possibly increased dopamine efflux in the nucleus accumbens(Di Chiara and Imperato, 1988), have become very popular tools for studying abuse liability and the psychopharmacology of the abused drugs. In this section, we begin with a very brief review of one important common factor. We then discussthe theoretical significance of this evidence in relation to decreasedI’. Drugs of abusehave many known and unknown acute effects. Most of theseeffects are specific to an individual drug, someare specific to a drug class,and a very few are common among virtually all abused drugs. Common factors are merely curiosities if they have no theoretical implications. 6. Value of a common factors approach

After discussing a cardiovascular profile that is common to many abused drugs, it is important to consider the potential value of this approach. We would argue that a common factors approach can function as a conceptual ‘sieve’ to screen drug effects for their methodological, etiological and theoretical significance. First, let us consider how abused drugs differ from one another. On the face of it, one might find it difficult

D.B. Newlin / Drug and Alcohol Dependence 37 (1995) 211-216

to conceive of an array of psychotropic drugs that are as different from each other as drugs of abuse. Decades of binding studies have shown that the receptors to which each drug binds, and more importantly, the receptor binding that is thought to be essential in the reinforcement function of each drug (e.g., Ritz et al., 1987) tend to be very different from each other. Before such studies, it may have appeared likely that all abused drugs operate through the same receptor, perhaps an endogenousopioid receptor. This is clearly not the case. These drugs, even within the same general (and arbitrary) drug class, have remarkably different pharmacokinetics. The biological fates of these drugs can differ to a great degreeeven when the samebasic receptor is involved. Finally, the acute and chronic effects of these drugs are also very different. An enormous literature documents these different effects, particularly in relation to any medicinal or toxicological properties of these drugs. In fact, it may be difficult to conceive of a conceptually related group of drugs that differ from eachother in as many respectsas the abused drugs differ from each other. Therefore, a common factors approach (Newlin, 1992)may operate as a sieveto determine for the researcher what drug characteristics are related to their abuse liability. This has practical value, in that one can then study new compounds to determine if they share these common factors. For example, is a new compound selfadminstered by rodents? Do animals consistently ‘choose’ to be in a chamber that has been associated with that drug effect?Does this new compound increase dopamine outflow in the nucleus accumbens?Finally, does the drug increase heart rate and decrease V? This determination may have basic theoretical significance (Newlin, 1994). Many drugs have been identified and studied exhaustively that all seemto have abuse liability. Why are these drugs abused when others are not? What is the brain mechanism(s) that determines abuse potential? What are the neuroanatomical and neurophysiological pathways that control drug-seeking behavior (Kalivas and Samson, 1992)? 7. Limitations of a common factors approach We have discussed some of the advantages of considering common factors (i.e., common factors reflect common mechanism). What are the the limitations of this approach? First, it is possible that the mechanisms and pathways that are essential in the abuse liability of thesedrugs simply are different for each drug or for each drug class. Perhaps the type of receptor determines the ultimate pathway that each drug takes to reinforcement. For example, it is possible that increased dopamine efflux in nucleus accumbens is epiphenomenal and plays no important role in substance abuse. A second limitation is that these common factors are

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common to most, but often not to all, abused substances. For example, THC and hallucinogens are not self-administered by animals (Mansbach et al., 1994), but these drugs are commonly abused by humans. We might suppose that subjective euphoria is a common factor in humans (Newlin, 1992),but the euphoria from smoking a cigarette in addicted smokersis subtle at best. Finally, we discussed the apparent evidence that damphetaminefails to show the samecardiovascular protile as other abused drugs, perhaps for artifactual reasons concerning the baroreceptor reflex. The question then becomeswhether theseexceptions are anomalies, important counter-examples to be studied for precisely this reason, or a basis to reject the common factor approach entirely. Finally, most of these common factors are studied in animals. In fact, they have been used to support the adequacy of the animal model of substance abuse for human abuse (Johanson and Schuster, 1981; Katz, 1990).Perhaps the transition from rodent or primate to human is too great. This question can be approached empirically if the technology, such as self-administration (Johanson and Schuster, 1981), is possible in humans (Grifliths et al., 1980). Acknowledgments The author is indebted to Srihari Tella for many interesting discussions concerning the cardiovascular mechanisms of cocaine, and to Charles Schindler for editorial assistance.This paper represents the views of the author (David B. Newlin), and not those of NIDA or the US Government. (In the Public Domain.) References Berne, R.M. and Levy, N.M. (1977)Cardiovascular Physiology, Third Ed., Mosby, St. Louis. Dellinger, J.A., Taylor, H.L. and Porges, S.W. (1987) Atropine sulphate effects on aviator performance and on respiratory heart period interactions. Aviat. Space Environ. Med. 58, 333-338. Di Chiara, G. and Imperato, A. (1988) Preferential stimulation of dopamine releasein the nucleus accumbensby opiates, alcohol, and barbiturates: studies with transcerebral dialysis in freely moving rats. Ann. N.Y. Acad. Sci. 473, 367-381. Fischman, M.W., Schuster, CR., Resnekov, L. et al. (1976) Cardiovascular and subjective effects of intravenous cocaine administration in humans. Arch. Gen. Psychiatry 33, 983-989. Grifiths, R.R., Bigelow, GE. and Henningfield, J.E. (1980) Similarities in animal and human drug-taking behavior. In: Advances in Substance Abuse: Behavioral and Biological Research, Vol. I (Mello, N.K., ed.). JAI Press, Greenwich, CT. Jaffe, J.H. (1991) Drug addiction and drug abuse. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 8th Ed. (Gilman, A.G., Rail, T.W., Nies, AS. et al., eds.). Pergamon Press, New York. Johanson,C.E. and Schuster,C.R. (1981)Animal models of drug selfadministration. In: Advances in Substance Abuse: Behavioral and Biological Research,Vol. I I (Mello, N.K., ed.). JAI Press,Greenwich, CT.

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