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Human conditioned compensatory response to alcohol cues: Initial evidence
Ah'ohol, Vol. 2, pp. 507-509, 1985. ~ Ankho International Inc. Printed in the U.S.A,
0741-8329/85 $3.00 + .00
Human Conditioned Compensatory Response to Alcohol Cues: Initial Evidence D A V I D B. N E W L I N D e p a r t m e n t o f Psychological Sciences, Purdue University, West Lafayette, I N 47907
NEWLIN, D. B. Human conditioned compensator)' response to alcohol cues: Initial evidence. ALCOHOL 2(3) 507-509, 1985.--Alcohol cues elicited a conditioned autonomic response that was opposite in direction to the effect of alcohol. Normal male social drinkers given placebo following four alcohol conditioning sessions showed a compensatory response consisting of decreased pulse transit time, vasomotor activity, and finger temperature. This pilot research supports the application of a classical conditioning model to human alcohol problems. Alcohol
Classical conditioning
Cardiovascular
Alcoholism
T H E conditioned response to a drug is often opposite in direction to the unconditioned drug effect. For example, alcohol produces hypothermia while cues repeatedly paired with alcohol elicit hyperthermia in rats [1, 4, 5]. Siegel [12] has developed a classical conditioning model of drug tolerance in which the conditioned compensatory response (CCR) is thought to subserve tolerance through partial cancellation of the pharmacological drug effect. The model has been supported by evidence in rats that morphine tolerance in situationally specific [9] and exhibits many of the characteristics of classical conditioning [10]. Direct evidence for the CCR in rats has come from experiments in which saline was injected in the presence of environmental cues previously paired with morphine [11] or alcohol [1, 4, 5]. Traditional nonpsychological theories of addiction cannot easily account for these data. Although the classical conditioning model has been extensively studied with animals, the limited human research has focused on conditioned tolerance rather than the CCR. In humans the CCR is functionally equivalent to an antagonistic placebo response, or a placebo response that is opposite in direction to the drug effect. Situational specificity of tolerance to alcohol has been found in normal drinkers using both autonomic [2] and cognitive measures [8], but the CCR to alcohol placebo was not demonstrated [8]. Elicitation and description of the CCR to alcohol cues in humans is a necessary step in applying the classical conditioning model t o human alcohol problems. We now report initial evidence for an autonomic CCR elicited by alcohol placebo in normal social drinkers. Normal subjects drank four times in a distinctive drinking room. According to the classical conditioning model, the distinctive drinking room would act as a compound conditioned stimulus after being repeatedly paired with alcohol. The subjects" only exposure to this room was while drinking or while intoxicated in the four conditioning sessions. Therefore, the drinking room was expected to elicit a CCR in the fifth (placebo) session that was opposite in direction to the effect of alcohol. The effect of alcohol would be shown in the first four sessions.
METHOD
Subjects Six college-age males with histories of normal social drinking participated as paid volunteers. They were recruited with a college newspaper advertisement for "males, age 21-31 for a paid psychology experiment." Potential subjects were screened on the phone to exclude those who reported any of the following: (1) drank less than once per week, (2) a history of an alcohol-related arrest or alcohol treatment, (3) current licit or illicit drug use, (4) current medical problem that might interact with alcohol, or (5) failure to agree to being driven home by the experimenter after every session after their blood alcohol level went below 0.04%. Apparatus The following autonomic measures were recorded on a Grass Model 79 Polygraph and Cromemco Z2-D microcomputer using standard techniques: (1) heart rate, measured with Beckman paste and electrodes in bipolar configuration; (2) pulse transit time, calculated from the R-wave to the upstroke (1/6 of pulse height) of the finger pulse; (3) finger pulse amplitude, using a Grass PTTL-F reflectance photoplethysmograph (second finger, left hand); and (4) finger temperature, measured by a YSI banjo thermistor (palmar surface, first phalange, first finger, left hand). Blood alcohol concentration (BAC) was measured with a Smith and Wesson 900a Breathylizer that was calibrated prior to the experiment. Music was played over a stereo Pioneer cassette recorder system. Procedure Subjects were exposed to four conditioning sessions with alcohol followed by a test session with placebo. Sessions were scheduled in the late afternoon or early evening at the same time for each subject on separate days within a two week period. Subjects were instructed not to eat within 4 hours of each session. In each session, physiological meas-
507
508
NEWHN
T ures were recorded continuously for a 10 minute resting baseline in a quiet laboratory room before drinking, and for 35 minutes during and after drinking in a separate subject room. This drinking room was made distinctive by low fluorescent lighting and moderately loud popular music. In the four alcohol conditioning sessions subjects received 0.5 g ethanol per kg bodyweight in the form of 100 proof vodka mixed 1:3 (by volume) with tonic water, deliberately mixed in their presence. A small amount of sweetened lime juice was added to help cover the taste of alcohol. They drank the fluid in a five minute period in the distinctive drinking room. The fifth session was a test session in which they drank a placebo drink consisting of debubbled tonic water poured from the vodka bottle mixed as above with regular tonic water. The rim of the subject's glass was wiped surreptitiously with vodka before pouring in order to provide the smell and taste of alcohol. All other procedures were identical in the conditioning and placebo sessions so that subjects were expecting alcohol in all five sessions. RESULTS
Data Reduction The cardiovascular data were stored on a beat-to-beat basis for offline analysis. These data were carefully screened to remove movement artifact, which consisted of less than 1% of the data. Five minute block means were calculated for each measure. The results are illustrated in Fig. 1 for the first four alcohol conditioning sessions compared to the fifth placebo session.
H Placebo o---.o Alcohol
I0" 8 6 E o.
4
"~ r~ -r
2 O' -2 -4 !
=
i
-71 -U
_ 64
E
-4
o.
0
I
2 4
-80
-I00 Blood Alcohol Concentration BAC was measured after every conditioning session, the mean BAC were 0.33%, 0.31%, 0.34%, and 0.33% for the first four sessions, respectively. These values, which did not signiticantly differ from each other, were consistent with expectation for the 0.5 g/kg dosage.
Appetitive Response Subjects drank during Block 3. This was reflected in an arousal-like response in all measures, with a rapid return to baseline in Block 4 when they stopped drinking. This appetitive response was similar for both alcohol and placebo drinking, suggesting that the response was not related to the pharmacological effect of alcohol.
CCR The direction of the placebo response was evaluated by nonparametric sign tests in which the direction of the response in each Block post-drinking (5, 6, 7, 8, and 9) was compared to the pre-drinking baseline in Blocks l and 2. This nonparametric test was necessary because the comparison between alcohol sessions and the placebo sessions could represent the effect of alcohol, the CCR, or both. The sign test evaluates the direction of the placebo response against its own baseline; it is not a comparison with alcohol sessions. The post-drinking placebo response was opposite in direction to the effect of alcohol. F o r pulse transit time, 29 of 30 blocks represented decreases, a result significantly different (p<0.05) from that expected by chance. F o r finger pulse amplitude and skin temperature, 30 of 30 blocks were decreases (p<0.05). The heart rate responses were inconsis-
-60' . m
g -4o <
o_ LL
-20.
oi 20~ 40
A~-2"01 " " -I .0 n 0.0 z
m~
1.0
BLOCKS ( 5 min) FIG. I. Heart rate (HR), pulse transit time (PTT), finger pulse ampli-
tude (FPA), and skin temperature responses to alcohol in four conditioning sessions and to placebo in a final test session. All measures are illustrated with "arousal" in the upward direction. Subjects actually drank during Block 3.
C O N D I T I O N E D C O M P E N S A T O R Y R E S P O N S E TO A L C O H O L tent, with 3 subjects showing primarily increases and 3 subjects showing primarily decreases. DISCUSSION The results indicated a placebo response that was opposite in direction to the effect of alcohol. This was particularly apparent for finger pulse amplitude and finger temperature where alcohol increased those functions in the familiar vasodilatory flushing response, and placebo decreased these functions. The most robust response was for pulse transit time. Placebo produced decreases of up to 10 msec 20 minutes after drinking. Alcohol itself produced only modest increases in pulse transit time. This may be due to the fact that although alcohol is a mild beta adrenoreceptor blocker [ 10], this was not a stress paradigm so that there were no sympathetic responses in pulse transit time for alcohol to block. All of the placebo responses were in the " a r o u s a l " direction. The significance of this directional trend is not yet clear. It appears that conditioning occurred to the relaxant properties of alcohol, producing an excitatory conditioned response. However, in an expectation paradigm in this laboratory [6] in which subjects drank malt beverage a single time with the expectation that it was alcoholic, the placebo response was clearly relaxant (i.e., decreased heart rate and electrodermal activity). Further research is needed to determine under what circumstances conditioning occurs to the relaxant and excitatory effects of alcohol. To the extent that conditioning is a procedure rather than a phenomenon, then the antagonistic placebo response found in this research was a conditioned response. It must be noted that the placebo response did not resemble either an appeti-
509
tive response (such as that seen in Block 3) or a stressinduced response because the placebo response did not include increased heart rate. This tends to/'tile out major competing interpretations of the effect. This preliminary study used the pre-drinking baseline as control. A replication study [7] has since been performed in which the placebo response following two alcohol conditioning sessions was compared to a separate group in which subjects drank a soft drink (that they knew did not contain alcohol) in three sessions. The pulse transit time and finger temperature responses were significantly different from the soft drink control. A final issue concerns the question of whether the antagonistic placebo response is due to prior laboratory conditioning, or is determined by simple expectation of drug. As noted above, an antagonistic placebo response has been found in a single session in this laboratory [6], although it involved different response systems. This issue is difficult to resolve because expectation and conditioning history are inextricably confounded in normal social drinkers and it is not at all clear that conditioning is anything more than the development of expectations. Conclusions This preliminary study found a conditioned response to alcohol placebo that was opposite in direction to alcohol. The results have been replicated [7], and new evidence linking the antagonistic placebo effect to clinical variables has begun. Research is needed in which the antagonistic placebo response is studied in problem drinkers and alcoholics.
REFERENCES I. Crowell, C. R., R. E. Hinson and S. Siegel. The role of conditioned drug responses in tolerance to the hypothermic effects of ethanol. Psychopharmacology (Berlin) 73: 51-54, 1981. 2. Dafters, R. and G. Anderson. Conditioned tolerance to the tachycardia effect of ethanol in humans. Psychopharmacology (Berlin) 78: 365-367, 1982. 3. Knott, D. H. and S. D. Beard. Changes in cardiovascular activity as a function of alcohol intake. In: The Biology of Alcoholism. Vo12: Physhdogy and Behavior, edited by B. Kissin and H. Begleiter. New York: Plenum Press, 1972. 4. Lr, A. D., C. X. Poulos and H. Cappell. Conditioned tolerance to the hypothermic effect of ethyl alcohol. Science 206:11091110, 1979. 5. Mansfield, J. G. and C. L. Cunninham. Conditioning and extinction of tolerance to the hypothermic effect of ethanol in rats. J Comp Physiol Psychol 94: 641-646, 1980. 6. Newlin, D. B. The antagonistic placebo response to alcohol cues. Psychophysiology 21: 590, 1984.
7. Newlin, D. B. Conditioned compensatory response to alcohol cues. Psychophysiology 21: 590, 1984. 8, Shapiro, A, P. and P. E. Nathan. Human tolerance to alcohol: The role of Pavlovian conditioning processes. Paper presented at the 91st Annual Convention of the American Psychological Association, Anaheim, CA, 1983. 9, Siegel, S. Morphine analgesic tolerance: Its situational specificity supports a Pavlovian conditioning model. Science 193: 323325, 1976. 10. Siegel, S. Morphine tolerance acquisition as an associative process. J Exp Psychol: Annu Behav Proc 3: 1073, 1977. ll. Siegel, S. Evidence from rats that morphine tolerance is a learned response. J Comp Physiol Psychol 89: 498.-506, 1975. 12. Siegel, S. Classical conditioning, drug tolerance, and drug dependence. In: Research Advances in Alcohol and Drug Problems, voi 7, edited by Smart, Glaser, Israel, Kalant, Popham and Schmidt. New York: Plenum Press, 1983.
0741-8329/85 $3.00 + .00
Human Conditioned Compensatory Response to Alcohol Cues: Initial Evidence D A V I D B. N E W L I N D e p a r t m e n t o f Psychological Sciences, Purdue University, West Lafayette, I N 47907
NEWLIN, D. B. Human conditioned compensator)' response to alcohol cues: Initial evidence. ALCOHOL 2(3) 507-509, 1985.--Alcohol cues elicited a conditioned autonomic response that was opposite in direction to the effect of alcohol. Normal male social drinkers given placebo following four alcohol conditioning sessions showed a compensatory response consisting of decreased pulse transit time, vasomotor activity, and finger temperature. This pilot research supports the application of a classical conditioning model to human alcohol problems. Alcohol
Classical conditioning
Cardiovascular
Alcoholism
T H E conditioned response to a drug is often opposite in direction to the unconditioned drug effect. For example, alcohol produces hypothermia while cues repeatedly paired with alcohol elicit hyperthermia in rats [1, 4, 5]. Siegel [12] has developed a classical conditioning model of drug tolerance in which the conditioned compensatory response (CCR) is thought to subserve tolerance through partial cancellation of the pharmacological drug effect. The model has been supported by evidence in rats that morphine tolerance in situationally specific [9] and exhibits many of the characteristics of classical conditioning [10]. Direct evidence for the CCR in rats has come from experiments in which saline was injected in the presence of environmental cues previously paired with morphine [11] or alcohol [1, 4, 5]. Traditional nonpsychological theories of addiction cannot easily account for these data. Although the classical conditioning model has been extensively studied with animals, the limited human research has focused on conditioned tolerance rather than the CCR. In humans the CCR is functionally equivalent to an antagonistic placebo response, or a placebo response that is opposite in direction to the drug effect. Situational specificity of tolerance to alcohol has been found in normal drinkers using both autonomic [2] and cognitive measures [8], but the CCR to alcohol placebo was not demonstrated [8]. Elicitation and description of the CCR to alcohol cues in humans is a necessary step in applying the classical conditioning model t o human alcohol problems. We now report initial evidence for an autonomic CCR elicited by alcohol placebo in normal social drinkers. Normal subjects drank four times in a distinctive drinking room. According to the classical conditioning model, the distinctive drinking room would act as a compound conditioned stimulus after being repeatedly paired with alcohol. The subjects" only exposure to this room was while drinking or while intoxicated in the four conditioning sessions. Therefore, the drinking room was expected to elicit a CCR in the fifth (placebo) session that was opposite in direction to the effect of alcohol. The effect of alcohol would be shown in the first four sessions.
METHOD
Subjects Six college-age males with histories of normal social drinking participated as paid volunteers. They were recruited with a college newspaper advertisement for "males, age 21-31 for a paid psychology experiment." Potential subjects were screened on the phone to exclude those who reported any of the following: (1) drank less than once per week, (2) a history of an alcohol-related arrest or alcohol treatment, (3) current licit or illicit drug use, (4) current medical problem that might interact with alcohol, or (5) failure to agree to being driven home by the experimenter after every session after their blood alcohol level went below 0.04%. Apparatus The following autonomic measures were recorded on a Grass Model 79 Polygraph and Cromemco Z2-D microcomputer using standard techniques: (1) heart rate, measured with Beckman paste and electrodes in bipolar configuration; (2) pulse transit time, calculated from the R-wave to the upstroke (1/6 of pulse height) of the finger pulse; (3) finger pulse amplitude, using a Grass PTTL-F reflectance photoplethysmograph (second finger, left hand); and (4) finger temperature, measured by a YSI banjo thermistor (palmar surface, first phalange, first finger, left hand). Blood alcohol concentration (BAC) was measured with a Smith and Wesson 900a Breathylizer that was calibrated prior to the experiment. Music was played over a stereo Pioneer cassette recorder system. Procedure Subjects were exposed to four conditioning sessions with alcohol followed by a test session with placebo. Sessions were scheduled in the late afternoon or early evening at the same time for each subject on separate days within a two week period. Subjects were instructed not to eat within 4 hours of each session. In each session, physiological meas-
507
508
NEWHN
T ures were recorded continuously for a 10 minute resting baseline in a quiet laboratory room before drinking, and for 35 minutes during and after drinking in a separate subject room. This drinking room was made distinctive by low fluorescent lighting and moderately loud popular music. In the four alcohol conditioning sessions subjects received 0.5 g ethanol per kg bodyweight in the form of 100 proof vodka mixed 1:3 (by volume) with tonic water, deliberately mixed in their presence. A small amount of sweetened lime juice was added to help cover the taste of alcohol. They drank the fluid in a five minute period in the distinctive drinking room. The fifth session was a test session in which they drank a placebo drink consisting of debubbled tonic water poured from the vodka bottle mixed as above with regular tonic water. The rim of the subject's glass was wiped surreptitiously with vodka before pouring in order to provide the smell and taste of alcohol. All other procedures were identical in the conditioning and placebo sessions so that subjects were expecting alcohol in all five sessions. RESULTS
Data Reduction The cardiovascular data were stored on a beat-to-beat basis for offline analysis. These data were carefully screened to remove movement artifact, which consisted of less than 1% of the data. Five minute block means were calculated for each measure. The results are illustrated in Fig. 1 for the first four alcohol conditioning sessions compared to the fifth placebo session.
H Placebo o---.o Alcohol
I0" 8 6 E o.
4
"~ r~ -r
2 O' -2 -4 !
=
i
-71 -U
_ 64
E
-4
o.
0
I
2 4
-80
-I00 Blood Alcohol Concentration BAC was measured after every conditioning session, the mean BAC were 0.33%, 0.31%, 0.34%, and 0.33% for the first four sessions, respectively. These values, which did not signiticantly differ from each other, were consistent with expectation for the 0.5 g/kg dosage.
Appetitive Response Subjects drank during Block 3. This was reflected in an arousal-like response in all measures, with a rapid return to baseline in Block 4 when they stopped drinking. This appetitive response was similar for both alcohol and placebo drinking, suggesting that the response was not related to the pharmacological effect of alcohol.
CCR The direction of the placebo response was evaluated by nonparametric sign tests in which the direction of the response in each Block post-drinking (5, 6, 7, 8, and 9) was compared to the pre-drinking baseline in Blocks l and 2. This nonparametric test was necessary because the comparison between alcohol sessions and the placebo sessions could represent the effect of alcohol, the CCR, or both. The sign test evaluates the direction of the placebo response against its own baseline; it is not a comparison with alcohol sessions. The post-drinking placebo response was opposite in direction to the effect of alcohol. F o r pulse transit time, 29 of 30 blocks represented decreases, a result significantly different (p<0.05) from that expected by chance. F o r finger pulse amplitude and skin temperature, 30 of 30 blocks were decreases (p<0.05). The heart rate responses were inconsis-
-60' . m
g -4o <
o_ LL
-20.
oi 20~ 40
A~-2"01 " " -I .0 n 0.0 z
m~
1.0
BLOCKS ( 5 min) FIG. I. Heart rate (HR), pulse transit time (PTT), finger pulse ampli-
tude (FPA), and skin temperature responses to alcohol in four conditioning sessions and to placebo in a final test session. All measures are illustrated with "arousal" in the upward direction. Subjects actually drank during Block 3.
C O N D I T I O N E D C O M P E N S A T O R Y R E S P O N S E TO A L C O H O L tent, with 3 subjects showing primarily increases and 3 subjects showing primarily decreases. DISCUSSION The results indicated a placebo response that was opposite in direction to the effect of alcohol. This was particularly apparent for finger pulse amplitude and finger temperature where alcohol increased those functions in the familiar vasodilatory flushing response, and placebo decreased these functions. The most robust response was for pulse transit time. Placebo produced decreases of up to 10 msec 20 minutes after drinking. Alcohol itself produced only modest increases in pulse transit time. This may be due to the fact that although alcohol is a mild beta adrenoreceptor blocker [ 10], this was not a stress paradigm so that there were no sympathetic responses in pulse transit time for alcohol to block. All of the placebo responses were in the " a r o u s a l " direction. The significance of this directional trend is not yet clear. It appears that conditioning occurred to the relaxant properties of alcohol, producing an excitatory conditioned response. However, in an expectation paradigm in this laboratory [6] in which subjects drank malt beverage a single time with the expectation that it was alcoholic, the placebo response was clearly relaxant (i.e., decreased heart rate and electrodermal activity). Further research is needed to determine under what circumstances conditioning occurs to the relaxant and excitatory effects of alcohol. To the extent that conditioning is a procedure rather than a phenomenon, then the antagonistic placebo response found in this research was a conditioned response. It must be noted that the placebo response did not resemble either an appeti-
509
tive response (such as that seen in Block 3) or a stressinduced response because the placebo response did not include increased heart rate. This tends to/'tile out major competing interpretations of the effect. This preliminary study used the pre-drinking baseline as control. A replication study [7] has since been performed in which the placebo response following two alcohol conditioning sessions was compared to a separate group in which subjects drank a soft drink (that they knew did not contain alcohol) in three sessions. The pulse transit time and finger temperature responses were significantly different from the soft drink control. A final issue concerns the question of whether the antagonistic placebo response is due to prior laboratory conditioning, or is determined by simple expectation of drug. As noted above, an antagonistic placebo response has been found in a single session in this laboratory [6], although it involved different response systems. This issue is difficult to resolve because expectation and conditioning history are inextricably confounded in normal social drinkers and it is not at all clear that conditioning is anything more than the development of expectations. Conclusions This preliminary study found a conditioned response to alcohol placebo that was opposite in direction to alcohol. The results have been replicated [7], and new evidence linking the antagonistic placebo effect to clinical variables has begun. Research is needed in which the antagonistic placebo response is studied in problem drinkers and alcoholics.
REFERENCES I. Crowell, C. R., R. E. Hinson and S. Siegel. The role of conditioned drug responses in tolerance to the hypothermic effects of ethanol. Psychopharmacology (Berlin) 73: 51-54, 1981. 2. Dafters, R. and G. Anderson. Conditioned tolerance to the tachycardia effect of ethanol in humans. Psychopharmacology (Berlin) 78: 365-367, 1982. 3. Knott, D. H. and S. D. Beard. Changes in cardiovascular activity as a function of alcohol intake. In: The Biology of Alcoholism. Vo12: Physhdogy and Behavior, edited by B. Kissin and H. Begleiter. New York: Plenum Press, 1972. 4. Lr, A. D., C. X. Poulos and H. Cappell. Conditioned tolerance to the hypothermic effect of ethyl alcohol. Science 206:11091110, 1979. 5. Mansfield, J. G. and C. L. Cunninham. Conditioning and extinction of tolerance to the hypothermic effect of ethanol in rats. J Comp Physiol Psychol 94: 641-646, 1980. 6. Newlin, D. B. The antagonistic placebo response to alcohol cues. Psychophysiology 21: 590, 1984.
7. Newlin, D. B. Conditioned compensatory response to alcohol cues. Psychophysiology 21: 590, 1984. 8, Shapiro, A, P. and P. E. Nathan. Human tolerance to alcohol: The role of Pavlovian conditioning processes. Paper presented at the 91st Annual Convention of the American Psychological Association, Anaheim, CA, 1983. 9, Siegel, S. Morphine analgesic tolerance: Its situational specificity supports a Pavlovian conditioning model. Science 193: 323325, 1976. 10. Siegel, S. Morphine tolerance acquisition as an associative process. J Exp Psychol: Annu Behav Proc 3: 1073, 1977. ll. Siegel, S. Evidence from rats that morphine tolerance is a learned response. J Comp Physiol Psychol 89: 498.-506, 1975. 12. Siegel, S. Classical conditioning, drug tolerance, and drug dependence. In: Research Advances in Alcohol and Drug Problems, voi 7, edited by Smart, Glaser, Israel, Kalant, Popham and Schmidt. New York: Plenum Press, 1983.