SYNAPSE 12228-235 (1992)

Alcohol Intoxication Does Not Change [llC]Cocaine Pharmacokinetics in Human Brain and Heart J.S. FOWLER, N.D. VOLKOW, J. LOGAN, R.R. MAcGREGOR, G.-J. WANG, AND A.P. WOLF Chemistry Department (J.S.F.,J.L., R.R.M., A.P.W.) and Medical Department (N.D.V., G.-J.W.),Brookhaven National Laboratory, Upton, New York 11973

KEY WORDS

PET, Cocaine distribution, Cocaine clearance, Cocaethylene

ABSTRACT There is increasing evidence that the combined use of cocaine and alcohol produces enhanced behavioral and toxic effects. We have used PET and tracer doses of [llC]cocaine in 7 normal human volunteers to assess if the distribution and clearance of cocaine are altered by alcohol intoxication. Each subject received 2 PET studies with [llC]cocaine (3-11 pg), one before and one during alcohol intoxication (1gkg). Regions of interest included the brain (n = 3) and heart (n = 4). Arterial plasma was assayed for unchanged cocaine and for labeled cocaethylene, a metabolite of cocaine found in individuals using cocaine and alcohol in combination (Hearn et al., 1991a). Alcohol intoxication did not change uptake and clearance or the steady-state distribution volume of [W] cocaine in brain (striatum, thalamus, and cerebellum) or in heart. Moreover, labeled cocaethylene was not detected in the 10 minute plasma sample. These results suggest that the acute enhancement of behavior and toxicity associated with the combined use of cocaine and alcohol is not due to an alteration in cocaine’s organ distribution or t o cocaethylene formation but may be related to an additive effect resulting from the direct actions of each of these drugs. Published 1992 Wiley-Liss, Inc. has been shown to prolong the blood and brain levels of INTRODUCTION The combination of cocaine with alcohol is one of the this drug (Jonsson and Lewander, 1973), and a recent most frequent patterns of combined drug use (Grant study has presented evidence that alcohol intoxication and Harford, 1990; Sands and Ciraulo, 1992).Alcohol is increases the plasma levels of cocaine given by nasal used in conjunction with cocaine to “come down” after a insufflation (Perez-Reyes and Jeffcoat, 1992). In addicocaine binge, and it is also used to change or intensify tion, it has been reported that the chronic administrathe effects of cocaine. The morbidity and mortality from tion of alcohol (2.5 mgkg) results in an increased brain: cocaine appear to be exacerbated by the concomitant plasma ratio for cocaine in rats at 10 minutes after use of alcohol, and recent epidemiological studies of cocaine administration, whereas the acute administracocaine fatalities have shown that the combined use of tion of a smaller dose of alcohol (0.4 mglkg)had no effect cocaine and alcohol results in an 18-fold increase in the (Vadlamani et al., 1984).The higher dose of alcohol had risk of sudden death (Boag and Havard, 1985; Smith, no effect on cocaine concentration in the plasma, heart, 1986; Rose et al., 1990). Although an increased risk of and lungs. It has been recently suggested that cocaethsudden death has been observed, the actual medical ylene, a behaviorally active and toxic cocaine metabobasis for death has not been described in the combined lite frequently found in the blood and tissue of individuals coadministering cocaine and alcohol, may play a use of cocaine and alcohol. role in the enhanced behavioral and toxic effects obOne can postulate a number of mechanisms which served with combined cocaine and alcohol use (Hearn could mediate the enhanced physiological potency of et al., 1991a; Jatlow et al., 1991; Woodward et al., 1991; the cocaine/alcohol combination. The ability of alcohol to affect drug behavior in vivo is well known (Rall, McCance-Katz et al., 1991; de la Torre et al., 1991; Katz 1990) and raises the possibility that cocaine’s metabo- et al., 1992). On the other hand, it has also been suglism and its pharmacokinetics may change in the pres- gested that the direct actions of each of the drugs may ence of alcohol and that this interaction may enhance produce additive behavioral and toxic effects (Masur behavioral effects and contribute to the observed synergistic toxicity. Such an effect has been demonstrated for amphetamine in that its coadministration with alcohol Received March 18,1992; accepted in revised form May 28,1992 PUBLISHED 1992 WILEY-LISS, INC.

PET STUDIES OF ALCOHOL AND COCAINE

et al., 1989). In the case of cocaine, the most frequent toxic effects are on the brain and the heart. Positron emission tomography (PET) is a nuclear imaging technique which allows the direct measurement of drug pharmacokinetics in the human body (Fowler et al., 1990). We have previously measured the uptake and kinetics of cocaine in the human brain and body using PET and ["Clcocaine. (Fowler et al., 1989; Volkow et al., 1992) We report here the use of PET and [llC]cocaine t o determine whether alcohol intoxication changes the pharmacokinetics of cocaine in brain and heart in normal human volunteers. Each subject received 2 PET scans with labeled cocaine, one before and one during alcohol intoxication. A measurement of the time course of labeled cocaine in arterial plasma accompanied each PET study. In addition, HPLC analysis was used to determine whether labeled cocaethylene (a behaviorally active metabolite of cocaine formed in the presence of alcohol) was present in the 10 minute plasma sample. Time-activity data from PET and the plasma input function were used to calculate a steadystate distribution volume (Logan et al., 1990) for cocaine before and during alcohol intoxication. METHODS Human PET studies Normal human volunteers (age 22-66, n = 7) were studied with [llClcocaine using the PET scanning and arterial blood sampling protocol described previously (Fowler et al., 1989). These subjects had no history of alcohol or drug abuse. Informed consent was obtained prior to the PET studies. Urine samples were taken prior to the PET studies to assure the absence of cocaine or cocaine metabolites. Each subject received 2 scans with ['lClcocaine (6-11 mCi, 3-11 kg), 2-2.5 hrs apart before and during alcohol intoxication. Three of the subjects had brain scans and 4 had heart scans. Alcohol (1g k g PO) was administered over a period of 45 minutes, as described previously (Volkow et al., 1990), when the first scan was completed. The second injection of [llClcocaine was given 40 minutes after the ingestion of alcohol. The scans were carried out as previously described (Fowler et al., 1989). Plasma analysis Arterial blood samples were obtained for measuring the blood alcohol concentration (National Psychopharmacology Laboratory Inc., Knoxville, Tennessee), for measuring total radioactivity and unchanged cocaine using the solid-phase extraction system (Volkow et al., 1992) and for HPLC analysis to determine whether labeled cocaethylene was present during alcohol intoxication. Since the solid-phase analysis system does not separate cocaine and cocaethylene, the plasma sample withdrawn at 10 minutes postinjection of labeled cocaine was subjected to HPLC analysis. Plasma samples (0.2 ml) were added to 0.5 ml of acetonitrile along with

229

carrier amounts of unlabeled cocaine and cocaethylene, the mixture was centrifuged, and the supernatant was injected onto a 150 x 4.6 mm Act-1 HPLC column, which was eluted with acetonitrile: 1%aq. ammonium hydroxide (60:40) at a flow rate of 0.4 mumin. The retention times were 16.7 minutes for cocaine and 22.2 minutes for cocaethylene. Mass was detected by ultraviolet absorption at 254 nM, and fractions were collected at each half-minute over a 28 minute collection time and counted in an automated well counter. Recoveries from the HPLC column were 90%. This analysis was carried out for 4 subjects in both the control and intoxicated states. Data analysis Regions of interest in the brain were obtained for the corpus striatum, cerebellum, thalamus, and cortex, as described previously (Fowler et al., 1989). Regions of interest in the heart were obtained for the left ventricle and the septum (Volkow et al., 1992).An input function was generated from the measurements of the total radioactivity in the plasma and was corrected for the amount of unchanged labeled cocaine. The tissue and plasma measurements were used to calculate steadystate distribution volumes for brain regions and for heart using a graphical analysis method developed for reversible systems (Logan et al., 1990). The steadystate distribution volume is given by

where K, and k, are transport constants between plasma and tissue, and tissue and plasma, respectively, and NS represents the ratio of constants (association/ dissociation) describing nonspecific binding. BMq and KD, refer to all receptor concentrations and equilibrium dissociation constants for specific binding. Providing that nonspecific binding and the ratio of Klk, are fairly constant, differences in the distribution volume between regions can be attributed to differences in BMKD1. RESULTS Blood alcohol levels were in the range of 0.11-0.18% following alcohol administration. Figure 1 shows timeactivity curves for the striatum for one of the subjects for [ "Clcocaine before and after alcohol intoxication. The average radioactivity concentration a t the time of peak uptake and clearance half-times (from time of peak uptake) in the striatum, thalamus, cerebellum, and heart are shown in Table I. Alcohol intoxication did not significantly affect the uptake, distribution, or clearance of [llC]cocaine in brain (striatum, thalamus, and cerebellum) in any of the 3 subjects investigated. The percentage of plasma radioactivity present as labeled cocaine a t 1,5,10, and 30 minutes was not significantly different before and during alcohol intoxication

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J.S. FOWLER ET AL.

0.01 2

0.01 0

n

0.008 0

$2

0.006

c1 ).c

0.004

0.002 0.0

0

5

10

15 20 Time (min)

25

30

35

Fig. 1. Time-activity curves for human striatum for [llClcocaine before (closed circles) and during (open circles) alcohol intoxication.

[95 2 2,92 2 6,69 % 15, and 37 2 5 (control) and 96 2 3, 92 6 , 69 2 15, and 42 % 8 (alcohol)]. In addition, plasma integrals for unchanged labeled cocaine over the time course of the PET experiment were similar before and during alcohol intoxication. Steady-state distribution volumes were calculated using PET timeactivity data for brain regions and for heart along with the plasma input function, and are shown in Table I along with the ratio of the plasma integrals. The ratio of the steady-state distribution volumes before and during alcohol was within the variation for repeated studies for the same subject without intervention (Logan et al., 1990). PET studies of the regions encompassing the heart showed that alcohol intoxication also did not influence the behavior of labeled cocaine in this organ. Figure 2 shows time-activity data from one subject for the heart before and during alcohol intoxication. HPLC analysis of a 10 minute plasma sample did not detect the presence of labeled cocaethylene (Fig. 3).

*

Toxicity of cocaine The most frequent medical complications from cocaine itself are related to its effects on heart and brain, and appear to be related, in part, to its sympathomimetic effects involving both central as well as peripheral processes (Tella et al., 1990; Calligaro and Eldefrawi, 1987; Pitts and Marwah, 1988; Fraker et al., 1990; Jones and Tackett, 1990; Wilkerson, 1988a,b; Kloner et al., 1992). In the heart, cocaine can induce toxicity by several mechanisms, such as induction of arrhythmias or changes in blood perfusion (Gradman, 1988; Crumb and Clarkson, 1990; Friedrichs et al., 1990), as well as direct interaction of cocaine with the myocyte (Peng et al., 1989; Przywara and Dambach, 1989). Cardiac arrhythmias, myocardial infarction, and ischemia secondary to cocaine have been reported in several clinical studies (Isner et al., 1986; Nademanee et al., 1989). Cardiac complications from cocaine have been documented in patients with and without evidence of heart disease (Gradman, 1988). The cardiac toxicity from cocaine has been mainly associated with its effects on the noradrenergic system and its local anesthetic properties (Kloner et al., 1992). The toxic effects of cocaine in the brain have been related to respiratory depression, seizure production, and cerebrovascular accidents (Jacobs et al., 1989).The effects of cocaine on the dopamine system (particularly the D1 receptors) have been associated with its lethality (Derlet et al., 1990; Ritz and George, 1990a). The actions on the serotonin system appear to relate to its ability to induce seizures (Ritz and George, 1990b).The high sensitivity of the locus coeruleus to cocaine (Pitts and Marwah, 1988) suggests that noradrenergic mechanisms may contribute to cocaine toxicity in the brain. In particular, the central noradrenergic effects could contribute to the deleterious actions of cocaine on cerebral blood flow (Preskorn et al., 1980). This is particularly relevant, inasmuch as we have been able to document profound, long-lasting changes in cerebral blood flow in chronic cocaine abusers (Volkow et al., 1988). Also several clinical reports have documented the association between cerebrovascular accidents and cocaine use (Levine et al., 1987,1990; Nolte and Gelman, 1989).

DISCUSSION The behavioral and toxic effects of cocaine itself are well documented, and there is mounting evidence that Interactions of alcohol and cocaine these effects are enhanced when cocaine is used in comAlthough the mechanisms by which cocaine produces bination with alcohol. In this study we considered the possibility that alcohol intoxication changes the phar- its behavioral and toxic effects and the medical basis for macokinetics of cocaine. We directly examined cocaine’s cocaine related deaths have been documented, there is uptake and clearance in the brain and heart of normal a general lack of information on the medical basis for, human volunteers with positron emission tomography. or the mechanisms underlying, sudden death in indiOur results are discussed below, along with a summary viduals using cocaine and alcohol in combination. The of the mechanisms of the toxicity of cocaine itself and frequency of the use of these 2 drugs in combination possible interactive and direct mechanisms for the ob- and the enhanced toxicity have combined to increase served synergistic effects of the cocaine/alcohol combi- the need to understand the mechanisms underlying their effects. nation.

PET STUDIES OF ALCOHOL AND COCAINE

231

TABLE I . Comparison of carbon-I1 concentration at time of peak uptake and clearance half-time for brain (n = 3) and heart (n = 4) before and during alcohol intoxication

Striatum

Thalamus

Cerebellum

HPnrt ~

Peak uptake (% injected dosekc) Control Alcohol

0.0078 t 0.0014 0.0077 ? 0.0018

Control Alcohol

16.7 t 1.4 18.1 i 2.5

0.0078 t 0.0013 0.0075 2 0.0013

0.0063 t 0.0010 0.0058 i 0.0015

0.0064 ? 0.0008 0.0067 ? 0.0007

Clearance half-time (min, from time of peak uptake) 14.5 i 1.5 12.0 2 3.2

12.2 t 2.9 12.3 i 4.2

6.9 2 1.3 5.8 i 0.7

'Peak uptake ranged 4.5-9.5 minutes (basal ganglia), 3 . W . 5 minutes (thalamus), and 2.5-3.5 minutes (cerebellum). Peak uptake in the heart occurred at 2-3 minutes. Percent dosdcc and clearance half-times are average 2 SDM. There were no significant differences between radioactivity concentration or clearance half-times between control and alcohol intoxication for the brain or heart (paired t test, two tail).

TABLE II. Steady-state distribution volumes and ratio of plasma integrals for ("CI cocaine in human subjects before and during alcohol intoxication

Study 1 2 3 4 5 6 7

Condition Control Alcohol Ratio' Control Alcohol Ratio2 Control Alcohol Ratio' Control Alcohol Ratio' Control Alcohol Ratio' Control Alcohol Ratio' Control Alcohol Ratio'

Steady-state distribution volume (mug-') Striatum Thalamus Cerebellum 5.19 5.46 0.95 4.52 4.28 1.06 5.59 5.21 1.07

3.64 3.66 0.99 3.12 2.95 1.06 3.73 3.44 1.08

Heart

3.09 3.11 0.99 2.52 2.43 1.04 3.31 3.02 1.10

Plasma ratio' 1.02 1.16 1.11

2.85 2.77 1.03 2.52 2.32 1.08 2.04 2.00 1.02 2.43 2.24 1.08

0.89 1.00 1.04

1.00

'Ratio of the integrals of the concentration of unchanged tracer (controllalcohol)in arterial plasma from the time of injection through 30 minutes. 'Ratio of steady-state distribution volumes before and after alcohol intoxication.

It is well known that alcohol can influence the pharmacokinetics and the pharmacodynamics of a drug (Rall, 1990; Hartmann et al., 1988). This can occur by a number of mechanisms, including alcohol mediated alteration of membrane fluidity and permeability (Wood and Schroeder, 1988), inhibition and induction of liver enzymes or the presence of liver disease (Lieber, 19881, alteration of plasma protein binding (Lane et al., 1985), or chemical reaction between alcohol and its metabolites and the drug, as in the formation of cocaethylene from cocaine (Hearn et al., 1991a; Dean et al., 1991; McCance-Katz et al., 1991; de la Torre et al., 1991; Boyer and Petersen, 1992). Each of these mechanisms could be anticipated to change the uptake and kinetics of cocaine and thus to change its bioavailability. A change in bioavailability could affect the tissue exposure to the drug, which could contribute to the enhanced behavioral and toxic properties of the cocaine/ alcohol combination. In this study we observed no effect of acute alcohol intoxication on cocaine pharmacokinetics in brain and

0.006

< 0

0.004

lo

n h !

0.002

0.0 Time ( m i n )

Fig. 2. Time-activity curves for [Wlcocaine for human heart before (closed circles) and during (open circles) alcohol intoxication.

J.S. FOWLER ET AL.

232

0

10

20

30

40

50

Fraction Number Fig. 3. HPLC trace showing W absorption for cocaine and cocaethylene and corresponding profile of radioactivity (bars) for human plasma at baseline (open bars) and during alcohol intoxication (solid bars).

heart. Even though we were not able to detect a change in cocaine pharmacokinetics, it is important to point out that these studies were carried out with tracer doses of cocaine in normal volunteers. In this respect, they do not reproduce the conditions used by the drug abuser who frequently coadministers cocaine and alcohol, and whose metabolism may be altered by long-term exposure to both of these drugs in pharmacologically significant quantities. Nonetheless, the studies do demonstrate that under conditions of acute alcohol intoxication, the exposure of the brain and heart to cocaine (administered as a tracer dose) does not change over a 45 minute period. Although in the present study the plasma integral for labeled cocaine did not significantly change during alcohol intoxication (Table II), a recent study of the effects of alcohol intoxication on the subjective and cardiovascular effects of snorted cocaine reported a significant increase in the plasma cocaine concentration over a two hour period suggesting increased bioavailability of cocaine (Perez-Reyes and Jeffcoat, 1992). Different routes of administration, quantities of cocaine administered, and study duration may account for the differences between the two studies. In addition to assessing cocaine pharmacokinetics, we also assayed plasma for labeled coaethylene at 10 minutes after the injection of labeled cocaine, since it has recently been suggested that the synergistic toxicity of cocaine and alcohol may be brought about by the formation of cocaethylene, a metabolite of cocaine found in individuals who use it in combination with alcohol (Hearn et al., 1991a). Cocaethylene is known to have a higher toxicity than cocaine (Hearn et al., 1991b). Although the extent to which cocaethylene contributes to cocaine toxicity is not known, a knowledge of its rate of

formation is of relevance in assessing its importance in contributing t o the acute toxicity of this combination. In this study we were unable to detect labeled cocaethylene formation at 10 minutes after the injection of [llC]cocaine to alcohol intoxicated subjects (10 minutes is the longest time point which could be examined due to the short half-life of carbon-11). Our inability to detect labeled cocaethylene at 10 minutes after the injection of labeled cocaine is consistent with the recently reported observation that cocaethylene formation is slow after the administration of cocaine and alcohol to humans, and the conversion is low (McCance-Katz et al., 1991; Perez-Reyes and Jeffcoat, 1992).Another recent study of the enzymatic basis for the transesterification of cocaine in the presence of ethanol reported that cocaine is transesterified in the presence of ethano1 in quantities that are quite low (Boyer and Petersen, 1992). From these results it is likely that if cocaethylene contributes to enhanced toxicity, its effects are unlikely to occur within a short period (30 minutes) after consumption of cocaine and alcohol because of its slow formation and low conversion. Nonetheless, cocaethylene has a slower clearance from brain and is metabolized more slowly by plasma cholinesterases, so that once it is formed it could be expected to accumulate (Fowler et al., 1992). Direct actions of cocaine and alcohol: Synergistic behavioral and toxic effects Our inability t o observe any effect of alcohol intoxication on cocaine pharmacokinetics suggest that it may be the direct actions of each of these drugs, and not their interaction, which results in enhanced behavioral and toxicological properties associated with their combined use. Direct effects which may contribute to their enhanced combined potency include dopaminergic and adrenergic stimulation, local anesthetic effects, and vasoconstrictive and baroreceptor properties. The enhanced acute behavioral effects of cocaine and alcohol used in combination may result from their additive effects on brain dopamine. The behavioral and euphorigenic effects of cocaine are associated with its enhancement of synaptic brain dopamine through blockade of the dopamine reuptake site which normally controls the concentration of synaptic dopamine (Ritz et al., 1987). Although alcohol has multiple effects on neurotransmitter activity in the brain, it has been shown that the acute administration of alcohol causes an increase in the concentration of dopamine in the brain (Seeman and Lee, 1974; DiChiara and Imperator, 1988). Thus the ability of both cocaine and alcohol to increase synaptic dopamine may play a role in the behavioral enhancement associated with their combined use. Additionally, it has recently been shown that alcohol administered in vivo produces bidirectional changes in dopamine reuptake sites in rat striatum, providing

PET STUDIES OF ALCOHOL AND COCAINE

yet another mechanism for changing synaptic dopamine levels (Hamdi and Prasad, 1991). The enhanced cardiotoxic effects from the combined use of cocaine and alcohol could arise from their additive stimulation of the adrenergic system. It is likely that both central and peripheral mechanisms are operative, with the increase in heart rate arising from adrenergic stimulation, both from cocaine’s blockade of the norephinephrine reuptake (Wilkerson et al., 1988a,b)and the acute stimulatory effect of ethanol on the sympathetic nervous system (Rall, 1990). It has been reported that the increase in heart rate in humans receiving a combination of cocaine and alcohol significantly exceeds the increase in heart rate following administration of either drug alone, suggesting that each of these drugs is enhancing the chronotropic effect of the other (Foltin and Fischman, 1989). This study also showed that combining cocaine, alcohol, and task performance resulted in an increase in heart rate greater than that observed following cocaine, ethanol, or task performance alone. Stimulation of the adrenergic system can also occur via the adrenal gland. Both cocaine and alcohol release adrenaline and noradrenaline from the adrenal gland (Pohoreckyand Brick, 1988).Release of catecholamines from the adrenals has been implicated as one of the mechanisms for the cardiotoxicity of cocaine (Nahas et al., 1991). The combined effects of these 2 drugs in the adrenals could lead to a higher release of adrenaline than when either of them is used alone. Cocaine toxicity has also been linked to its vasoactive properties, which can induce vasoconstriction, hemorrhages, and stroke (Altura and Altura, 1987). Alcohol accentuates the vasoconstricting properties of drugs (Rall, 1990) and also has direct vasoactive properties (Altura and Altura, 1987). Both cocaine and alcohol are known to have anesthetic properties (Ritchie and Green, 1990; Rall, 1990). These anesthetic properties can decrease the activity of excitable tissues in the heart. (Thomas et al., 1991)This will translate into depression of myocardial tissue. Coadministration of these 2 drugs would increase the depressant action of either one of them alone. Cocaine has also been shown to disrupt baroreceptor activity via its disruption of the renin-angiotensin system (Trouve et al., 1991). Alterations in blood pressure secondary to alcohol ingestion when occurring in an individual whose homeostatic mechanism for regulation of blood pressure was disrupted by cocaine could result in an inability to compensate for the change, resulting in potentially fatal consequences. In summary, this study showed that alcohol intoxication does not significantly affect the short-term distribution and clearance of cocaine in brain and heart. In addition, we failed to detect the formation of cocaethylene in the plasma at 10 minutes after [l’Clcocaine injection. These results suggest that the acute enhance-

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ment of the behavioral and toxic effects of the cocainel alcohol combination is not caused by a change in the residence time of cocaine in the brain or heart, and argues against a role for cocaethylene as a mediator of the acute behavioral and toxic properties of this combination. In explaining the enhanced behavioral and toxic effects seen with coadministration of cocaine and alcohol, one has to be aware that they are not specific for this particular drug combination. The combination of other stimulant drugs with alcohol or other sedative hypnotics had previously been shown to enhance the behavioral and toxic effects of the individual drugs (Rech et al., 1976; Iverson et al., 1975; Coleman and Evans, 1975). For example, coadministration of amphetamine with alcohol greatly enhanced its lethality, particularly when animals were subjected to stressful conditions (Rech et al., 1976).The latter studies and the current findings emphasize the need to consider that the direct actions of alcohol and of cocaine (or other stimulants) may mediate the enhanced behavioral and toxic properties of their combination. It is also important to consider that the nature and intensity of the behavioral and toxic effects may also depend on the relative doses and timing of administration of the 2 drugs, the drug history of the individual (Antelman et al., 19911, and the conditions of drug administration (Rech et al., 1976). Clearly, the factors contributing to the enhanced toxicity with the combined use of cocaine and alcohol are complex and require further study. ACKNOWLEDGMENTS This work was carried out at Brookhaven National Laboratory under contract DE-AC02-76CH00016with the U.S. Department of Energy and was supported by its Office of Health and Environmental Research and was also supported by the National Institutes on Drug Abuse (DA 06278) and National Institutes of Health (NS 15638). We thank Donald Warner, Naomi Pappas, Payton King, David Schlyer, Robert Carciello, Babe Barrett, David Alexoff, Elizabeth Jellett, Colleen Shea, Karin Karlstrom, Thomas Martin, Noelwah Netusil, and Theodore Johnson for their advice and assistance in various aspects of this work. REFERENCES Altura, B.M. and Altura, B.J. (1987) Peripheral and cerebrovascular actions of ethanol, acetaldehyde and acetate. Relationship to divalent cations. Alcohol., Clin. Exp. Res., 11:99-111. Antelman, S.M., Caggiula, A.R., Kocan, D., Knopf, S., Meyer, D., Edwards, D.J., and Barry, H. Jr. (1991) One experience with “lower”or “higher” intensity stressors, respectively enhances or diminishes responsiveness to haloperidol weeks later: implications for understanding drug variability. Brain Res., 566:276-283. Boag, F. and Havard, C.W.H.(1985) Cardiac arrhythmiaand myocardial ischaemia related to cocaine and alcohol consumption. Postgrad. Med. J., 61:997-999. Boyer, C.S. and Petersen, D.R. (1992) Enzymatic basis for the transesterification of cocaine in the presence of ethanol: evidence for the participation of carboxylesterases. J. Pharm. Exp. Ther., 260:939945. Calligaro, D.O. and Eldefrawi, M.E. (1987) Central and peripheral cocaine receptors. J. Pharm. Exp. Ther., 243:61-68.

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