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Appetitive nature of drug cues confirmed with


physiological measures in a model using
pictures of smoking

Article in Psychopharmacology · July 2000


DOI: 10.1007/s002130000404 · Source: PubMed

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Psychopharmacology (2000) 150:283–291
Digital Object Identifier (DOI) 10.1007/s002130000404

O R I G I N A L I N V E S T I G AT I O N

A. Geier · R.F. Mucha · P. Pauli

Appetitive nature of drug cues confirmed with physiological measures


in a model using pictures of smoking

Received: 22 September 1999 / Accepted: 31 January 2000 / Published online: 26 April 2000
© Springer-Verlag 2000

Abstract Rationale: In smokers, pictures of smoking Key words Smoking · Nicotine · Cue · Motivation ·
that increase desire for a cigarette are described as pleas- Deprivation · Expectancy · Startle reflex · EMG ·
ant rather than unpleasant. This suggests that these Corrugator · Zygomatic · Craving · Relapse · Age
smoking cues may be appetitive and not withdrawal-like
or aversive as held by traditional theories of drug cue
formation. Objective: Cues for smoking were examined Introduction
using physiological measures of motivational valence.
Methods: Non-deprived smokers, deprived smokers and Drug cues have a well known role in the maintenance
deprived smokers who expected to smoke (n=54) viewed and reinitiation (relapse) of drug intake in the addictive
a computer screen presenting experimental and control individual. From the animal literature, it is assumed that
scenes (experiment 1). The acoustic startle reaction and they arise through multiple conditioning mechanisms
activity of the corrugator and the zygomatic facial mus- (Wise 1987; Drummond et al. 1990; O'Brien et al. 1992;
cles were then measured after onset of smoking cues and Nader et al. 1997; Nesse and Berridge 1997) and it re-
standardized pleasant, neutral or unpleasant control mains a challenge to identify the relative role of the dif-
scenes. Individuals who never smoked (n=18) were also ferent processes in the dependent human (Mucha et al.
used to test for cue effects on startle (experiment 2). 1998). Pictures of cigarette smoking increased the desire
Results: No evidence was found that smoking cues were to smoke a cigarette (Mucha et al. 1999). However, they
aversive in smokers. The smoking cues affected the star- did so without being described as unpleasant. This con-
tle responses and corrugator activity in a way similar to firmed the appetitive nature of smoking cues noted from
that of pleasant control material but significantly differ- other studies on pictures or videos of smoking
ent from that of unpleasant material; the cue effects on (McDermut and Haaga 1998; Bushnell et al. 2000), con-
zygomatic activity was most similar to that of neutral ditioned smoking cues (Mucha et al. 1998; Lazev et al.
material. The general pattern of effects was not influ- 1999) and cues based on actual smoking (Zinser et al.
enced by overnight smoke deprivation, expectancy to 1999). Thus, these data are inconsistent with traditional
smoke or smoke repletion, but it was different in never pharmacological/adaptive theories of drug cues, which
smokers where the smoking scenes were found to be assume cues to elicit aversive reactions similar to adap-
similar to unpleasant control scenes. Conclusions: Non- tive responses underlying withdrawal (Wikler 1973;
subjective measures of motivational valence further sug- Solomon and Corbit 1974; Siegel 1975; 1989; Poulos
gest that drug cues are conditioned stimuli having appet- and Cappell 1991; Koob et al. 1997). More importantly,
itive effects. Startle response modulated by drug cues it provides direct evidence for incentive motivational
may be useful for probing motivational processes under- theories of drug cues in the human (see Stewart et al.
lying dependence in the human. 1984; Wise 1987; Robinson and Berridge 1993).
The present study was designed to extend the fact that
previous work with pictures of cigarette smoking was
A. Geier · R.F. Mucha · P. Pauli largely based on subjective information about the pic-
Institute of Medical Psychology & Behavioural Neurobiology, tures (see Mucha et al. 1999; Warburton 1999). Self-re-
University of Tuebingen, Gartenstrasse 29, 72074 Tuebingen,
Germany ported information on alcohol and drug dependence from
the addicts themselves is not always accurate (see Sobell
R.F. Mucha
Department of Addictive Behavior and Addiction Medicine, and Sobell 1990; Lamb et al. 1991) and are seen as trou-
Central Institute for Mental Health, J5, 68159 Mannheim, blesome as primary support for theoretical ideas (Altman
Germany et al. 1996, p. 293). This may represent in part the long
284

recognized secondary gain of under- or overplaying the for different goal objects were collected to confirm ma-
true nature of the disorder by the addict (Kolb and nipulations of smoke intake. To test whether any effects
Himmelsbach 1938). However, Robinson and Berridge were indeed due to experience with smoking and thereby
(1993) also indicated a theoretical reason for the inaccu- conditioning, we carried out a second experiment in per-
racy of subjective reports. They suggest that the develop- sons who never smoked.
ment of dependence involves a biologically based un- The overall magnitude of the ASR varies greatly over
coupling of processes responsible for subjective descrip- individual subjects and test conditions (see Bradley et al.
tions and for behavior responses to drugs and drug cues. 1993; Müller et al. 1998). Although the magnitude of the
There was an attempt to confirm the appetitive effects of baseline startle response has been shown not to affect the
smoking cues using laterality of frontal EEG responses modulation of the startle magnitude by normal motiva-
(Zinser et al. 1999). However, methodological and inter- tional/emotional stimuli (Bradley et al. 1993), this has
pretative problems of this procedure (Hagemann et al. not been examined for any modulation of ASR by drug-
1998) indicate a need for further work. related stimuli in the dependent individuals. Therefore,
Therefore, we report on the use of the acoustic startle the main data in experiment 1 were also evaluated for
reflex (ASR) as a non-subjective measure of motivation- cue modulation after splitting the smokers into those
al valence of pictures of smoking cues. The ASR is a having short and long startle responses.
species-typical reaction to a loud burst of sound. It has
been routinely used in the animal literature to test for the
motivational effects of conditioned stimuli (Koch and Materials and methods
Schnitzler 1997; Fendt and Fanselow 1999) and it has
the important feature that it may be used in the human to Subjects
indicate the motivational status of pictures. Standardized Experiment 1 was carried out with 54 (18 women) right-handed
scenes varying from unpleasant to pleasant linearly de- smokers. Eighteen individuals (nine women) who reported con-
creased the magnitude of the ASR in a variety of valida- suming two or fewer cigarettes in their entire lives (never smok-
tion studies (Lang et al. 1990; Lang 1995; Hamm et al. ers) were recruited for experiment 2. Initial screening was with the
1997). Together with the standardized pictures, the ASR Fagerström Tolerance Questionnaire (FTQ; Fagerström 1978) and
questions about lifetime smoking in the two experiments, respec-
was an effective probe for motivational effects of psy- tively. In a recruitment/demonstration session, subjects gave writ-
chopathological states and drugs (Patrick et al. 1996; ten consent for ethically approved procedures following tests for
Hamm et al. 1997). The ASR has also been used to ex- CO and the ASR. Eight subjects in the first and one in second ex-
amine smoking and nicotine effects in humans (Elash et periment were excluded during recruitment due to a lack of the
startle response.
al. 1995; Kumari et al. 1996; Della Casa et al. 1998;
Müller et al. 1998), but it has not been applied to the mo-
tivational effects of smoking pictures. Stimulus material and stimulus presentation
The first of two experiments examined the ASR dur-
ing smoking pictures that evoked maximal effects on de- The pictures in experiment 1 comprised 64 colour slides, present-
ed with 35 cm computer monitor (Sony Multiscan 17sf II) at 1.5 m
sire to smoke (Mucha et al. 1999). The effect on facial in front of the subject. Sixteen pictures depicted cigarette smok-
muscle activity was also measured, given that the corru- ing. They were chosen from those tested in a previous study as
gator muscle (“frown muscle”) is selectively activated evoking the highest desire to smoke; they depicted the preparation
by unpleasant pictures and the zygomatic muscle (“smile for or the start of smoking (Mucha et al. 1999). Control pictures
were from the International Affective Picture System (IAPS; Lang
muscle”) by pleasant ones (Lang et al. 1993). The sub- 1995) depicting 16 neutral (2840, 5534, 6150, 7000, 7002, 7006,
jective and physiological effects of the cues were com- 7010, 7034, 7050, 7090, 7150, 7217, 7025, 7030, 7040, 7233), 16
pared to responses evoked by standardized pictures de- pleasant (1710, 4660, 5621, 5700, 5910, 7270, 7502, 8030, 8080,
rived from the International Affective Picture System 8200, 8370, 8380, 8190, 8420, 5480, 8470) and 16 unpleasant
(1300, 3060, 3102, 3170, 3530, 6212, 6230, 6313, 9410, 9570,
(Lang 1995; Mucha et al. 1999). Experiment 1 was actu- 9910, 9921, 3000, 3150, 6560, 9252) objects or scenes; criteria for
ally carried out in two groups of deprived and in one the choice of the pictures were reported previously (Mucha et al.
group of non-deprived smokers organized to ensure dif- 1999). The pictures were organized in two equivalent sets of 32
ferent conditions of smoke deprivation and repletion. pictures (one for each of two test blocks) in five pseudorandomis-
The manipulation of smoke deprivation was considered ed orders. Pictures were presented for 7 to 8 s (mean 7.5 s), fol-
lowed by a darkened monitor for 16.5 to 25.5 s (mean 21 s). An
important, given that withdrawal may increase the sa- ASR was evoked during two-thirds of the pictures 2.5, 4.0 or 5.5 s
lience of drug cues (Markou et al. 1993; Toates 1994; after picture onset. Experiment 2 used only half of the pictures.
Zinser et al. 1999) and it was found to have a small but
significant effect on subjective responses to our smoking
Data recording
pictures (Mucha et al. 1999). One group of deprived
smokers were allowed to replete themselves by smoking Unless otherwise stated, the recording conditions were as previ-
during the study to control for manipulation of depriva- ously described (Müller et al. 1998). Briefly, the startle response
tion and concomitant changes in expectancy of con- elicited by a 50-ms burst of 95 dB white noise using Beyerdynam-
ic (DT 331) headphones was measured digitally (Vitaport, Becker
sumption (Turkkan et al. 1989; Droungas et al. 1995). Engineering, Karlsruhe, Germany) as EMG activity from the left
Heart rate (HR) and alveolar carbon monoxide (CO) to- orbicularis oculi muscle using Hellige miniature electrodes. Sam-
gether with subjective measures of emotion and desire pling was at 512 Hz and the high- and low-pass filter settings were
285
Fig. 1 Schema of test session
in experiment 1 as a function of
time of test (min) for subjects
prepared for physiological re-
cording. DD deprived-
deprived, DS deprived-smoked,
SS smoked-smoked, HR heart
rate measurement, CO carbon
monoxide test, and SUBJ sub-
jective tests

0.015 s and 2200 Hz, respectively. The signals were then rectified, available responses for a particular test condition. Boost in CO
integrated and stored at 256 Hz. EMG activity was similarly re- was the difference in CO level between start and end of the
corded from the left corrugator supercili and the zygomaticus ma- pause. HR (beats per min) was scored 10 s before and after physi-
jor and stored at 16 Hz. ological testing.
In experiment 1, recordings (4 Hz) we also made of heart rate
(HR) and levels of CO were measured. In both experiments, mo-
mentary states of pleasure/displeasure and arousal/relaxation be- Data analysis and experimental design
fore and after the physiological testing were scored on 9-point
scales using an electronic version of the Self-Assessment Manne- In both experiments, the data were parametrically evaluated with
quin (SAM; Lang 1995). Visual analog scales (100 mm, VAS) an overall ANOVA followed by appropriate mean tests. Expected
were used to score desire to smoke, eat, drink water and drink al- results were evaluated with a priori tests using appropriate error
cohol. Momentary pleasure and arousal evoked by the test pictures terms derived from the ANOVA. Tests for non-predicted mean dif-
were scored with pencil and paper using 9-point scales (Mucha et ferences were carried out with Tukey's HSD tests. Where neces-
al. 1999). sary, family-wise error rates and Dunn's procedure were used
(Kirk 1995). The level of significance was P<0.05 (two-tailed).
The data were typically presented as means of the subjects' scores
Experimental procedures in a particular condition; SEs were presented for between-group
designs only.
In experiment 1, one of three groups matched for age, years In experiment 1 most parameters were evaluated using a (3×2)
smoked, FTQ and recruitment CO level was instructed to arrive in mixed ANOVA with three levels of group and two levels of a re-
the laboratory without any deprivation (SS); the subjects of the DS peated measure; the demographic characteristics were evaluated as
and DD groups arrived 12 h smoke deprived. After preparation for a fully between-group design. The startle and facial EMG data
recording, the SS and the DS subjects were informed that they were evaluated as a (3×2×4) mixed design with three groups, two
could smoke in the 15-min pauses separating the testing; the DD blocks and four picture categories. Facial EMG data had a log
were told that there would be no smoking during the study. transformation prior to statistical analysis as recommended by
The subjects were then tested for CO, desire to consume and Epstein et al. (1990). Similar designs were used for pleasure and
momentary pleasure/displeasure and arousal/relaxation (see Fig. 1). arousal evoked by the pictures except for no block effect. Effects
Then they were informed about and briefly habituated to the star- of the reference/control pictures were predicted, but their contrasts
tle/picture test using one smoking, pleasant, neutral and unpleas- with those of the smoking cues were not. Evaluation of experi-
ant scene and three startle probes. The subjects were instructed to ment 2 was similar except for the lack of the group variable.
view a picture and ignore any noises from the headphones. A com- In a further analysis of the data of experiment 1, we tested a
puter then presented the pictures for the two blocks. The first methodological hypothesis that the general magnitude of the star-
pause started and ended with a CO test. The subjects could walk tle response affected the pattern of responses seen to smoking and
about and all DS and all but two SS subjects smoked (see Fig. 1). control pictures. All data for each subject were first averaged to
Following the end of the second block, the subjects were again yield an overall estimate of the startle magnitude. The subjects
tested for CO, desire to consume and momentary pleasure/displea- were then split using the median startle response of the entire
sure and arousal/relaxation (see Fig. 1). Following another pause, group into those having longer and shorter startle responses. This
the subject was then to view each picture from the study for as was then followed by analyses of the overall startle responses
long as desired and then rate their momentary pleasure and arous- (averaged for the two blocks), momentary pleasure and momen-
al. tary arousal using 2 (magnitude)×4 (category) mixed ANOVAs.
In experiment 2, testing for smoke repletion was not necessary We also compared the general subject characteristics of the two
so only the first block from experiment 1 was run. Measures relat- new groups, including nicotine dependence, age and years of
ed to smoking were not taken. In addition, only the startle re- smoking.
sponse was measured in experiment 2.

Data reduction Results


A startle response was the difference between the maximum of a Experiment 1: effects of cues in smokers
response starting within 20–51 ms after startle probe onset and
the baseline (average over the 51 ms prior to a probe). Data for a
particular startle probe were not included given a possible extra- Demographic characteristics of subjects
neous eye movement during the baseline period and during the
first 19 ms of the startle probe; approximately 5% of the startle The three experimental groups had comparative ages, re-
responses were discarded. The zygomatic and the corrugator ac- ported similar years of smoking and had a comparable
tivity was the difference between the maximum EMG response
seen over the 2.5 s after and the 1 s prior to picture onset. The degree of dependence as measured by the FTQ (see
startle and the facial EMG responses were expressed as arbitrary Table 1). None of the differences was significant [all
A-D units and an individual's actual score was the average of F(1,51)<0.1].
286

Effects of deprivation/repletion on measures of HR, CO, ing; individual values ranged from 5.2±0.4 to 6.2±0.4
desire for cigarettes and other goal objects [all F(1,51) values <1.3]. Analysis of momentary plea-
and momentary emotional state sure/displeasure revealed a significant interaction of time
and group [F(1,51)=3.5, P<0.04]. As we had expected,
As noted in Table 2 the non-deprived subjects started the the SS group (3.3±0.4) reported the most pleasurable
study with a higher mean HR than the DD and the DS state which was significantly different from that of the
[both F(1,51)>4.7, P<0.05]. There was also an increase DS group (4.8±0.3) [F(1,51)=5.0, P<0.05]; however,
in the HR for the DS group [F(1,51)=31.5, P<0.001]. there was no significant difference between the SS and
The initial CO levels of the deprived groups (DD and the DD groups (3.8±0.4). The values gathered after
DS, see Table 2 ) were lower than those of the non-de- smoking for the DS (3.8±0.5) and the SS group (4.3±0.5)
prived SS group [both F(1,51)>85, P<0.001] and re- could not confirm a change over the testing. However,
mained so throughout the testing. The DS and SS groups inspection of the data from the DS and SS groups did
also smoked between the blocks of the study. This was suggest the presence of a significant interaction effect
not clear from the CO values measured before and after which was confirmed by analyzing the data from the
physiological testing but was seen from a measure of CO these two groups separately [F(1,34)=5.4, P<0.03].
boost during the pause. The respective values were
3.6±0.7 and 2.8±0.5 ppm for the DS and SS groups [both
t(17)>5.1, P<0.001]. Startle reflex effects of the experimental pictures
Self-reported measures of desire for a cigarette was
less in the non-deprived group than in the two deprived There was a clear main effect of category of slide on the
groups (see Table 2 ); for example, the overall mean de- startle reflex magnitude [F(3,153)=7.4, P<0.001] but no
sire of the SS group was significantly less than that of significant overall group effect [F(2,51)=0.4], nor inter-
the DD [F(1,51)=5.4, P<0.05]. Similarly, over the test action of group with picture category [F(6,153)=0.7] or
session there was a drop in the desire to smoke in both block [F(6,153)=2.0]. The overall effect of block was
groups that smoked [both F(1,51)>14.6, P<0.001]. The significant [F(1,51)=22.1, P<0.001], which probably re-
specificity of these effects was confirmed from a mea- flected a habituation effect; the mean difference between
sure of desire for drinking which did show an overall ef- the startle responses measured in the first and second
fect of time [F(1,51)=5.4, P<0.03] but no interaction of block for all 54 subjects was –7.5±0.14 A-D units. Since
time with group [F(1,51)=0.3]. Also, the desire for alco- the block manipulation did not interact appreciably with
hol showed no appreciable change. However, desire to any other variable, it was ignored, and only the data for
eat showed an overall effect of time [F(1,51)=11.4, the category of pictures were presented in Fig. 2. These
P<0.002] together with an unexpected interaction of were presented as a contrast between the effects of the
time and group [F(2,51)=4.4, P<0.02]. Post hoc analyses smoking cues and those of the reference pictures from
indicated that DD group showed an increase in desire to the IAPS.
eat (Tukey's HSD test, P<0.05) which was not apparent The startle magnitude was modulated as previously
in the two groups that smoked (see Table 2 ). reported by the three categories of reference pictures
Subjective measures of momentary arousal/relaxation from the IAPS. The unpleasant pictures had stronger
showed no effect before or over the physiological test- startle responses than the pleasant pictures
[F(1,153)=9.5, P<0.004]. The mean of the neutral pic-
tures was also significantly greater than that of the posi-
Table 1 Demographic data (mean±SE) for subjects in experiment 1. tive IAPS pictures [F(1,153)=7.6, P<0.008], but not ap-
FTQ Fagerström Tolerance Questionnaire. DD subjects deprived preciably different from the unpleasant ones [F value
before and during testing, DS subjects deprived before but not dur- <0.2)]. Smoking pictures had startle responses similar to
ing testing, SS subjects allowed to smoke before and during testing
those of the pleasant pictures rather than to the unpleas-
Age(years) Years smoked FTQ ant ones (see Fig. 2); thus, the mean startle measured
during the smoking pictures was significantly lower than
DD 24.6±1.0 7.9±1.1 6.4±0.3 that taken during the unpleasant control pictures [Tu-
DS 25.5±1.5 7.2±1.4 5.9±0.3
SS 25.3±1.6 7.9±1.0 6.5±0.3
key's HSD test, P<0.05]. The appreciable difference be-
tween the neutral and smoking pictures failed to meet

Table 2 Mean (±SE) heart rate


(HR), alveolar carbon monox- HR (bpm) CO (ppm) Cigarettes Food Water Alcohol
ide (CO) and desire for con-
sumption of various goal ob- DD Before 69.8±2.8 7.3±0.7 64.5±7.5 49.3±7.3 74.3±4.8 10.3±4.0
jects measured before and After 74.6±2.4 7.1±0.6 71.5±6.0 69.1±7.0 79.6±4.3 11.2±4.7
again after the physiological DS Before 70.4±2.1 7.7±0.8 75.8±4.2 45.2±7.6 67.1±7.1 7.2±3.1
testing. See Table 1 for further After 83.7±2.2 9.8±1.0 58.0±6.0 50.9±7.3 70.9±6.4 7.6±4.2
details SS Before 79.5±3.8 26.8±5.3 44.8±6.8 50.2±7.3 60.8±5.0 12.3±4.3
After 79.8±3.7 19.8±2.2 26.8±5.3 51.5±7.4 68.8±6.4 11.3±4.6
287

Fig. 2 Mean startle magnitude (A-D units) measured during pic-


tures depicting preparation of smoking (solid horizontal line:
smoking cues) as compared to startle magnitudes seen during
three types of non-smoking, control pictures depicting standard-
ized unpleasant, neutral or pleasant scenes (see text). All data
were gathered in experiment 1 from repeated tests in 54 smokers,
collapsed across three groups and two test blocks

Fig. 3 Mean change in EMG activity (A-D units) of the corruga-


our present criterion of significance; however, given an tor (upper panel) and the zygomatic muscle (lower panel) after
argument that testing (see Materials and methods) was onset of smoking and control pictures during first (broken line)
unduly stringent, we note that an F test yielded a value and second block (solid line) of testing in experiment 1. For fur-
of 6.1 (df=1, 153). ther details see Fig. 1

Effects of the experimental pictures on the facial EMG pictures [F(1,153)=4.9, P<0.05]. In this block, the mean
for the smoking cues fell between the means for the un-
It was confirmed that the corrugator muscle was affected pleasant and neutral pictures, but it was not significantly
by picture category [F(3,153)=19.9, P<0.001] but not by different from that of any of the control cues.
group, block or the block by group interaction [all
F<1.2]. The block by picture category interaction did ap-
proach significance [F(3,153)=2.3, P<0.09]; however, Pleasure and arousal evoked by experimental pictures
this did not affect the relation of the control to the smok-
ing pictures (see Fig. 3, top panel). Mean comparisons For momentary pleasure evoked by the pictures, there
confirmed that the corrugator was primarily sensitive to was a main effect of picture category [F(3,153)=173.2,
unpleasant pictures. The overall mean for the unpleasant P<0.001; see Fig. 4, top panel]. There was no effect of
pictures was significantly higher than that of the pleasant group [F(2,51)=0.02] and no significant interaction of
[F(1,153)=17.5, P<0.001] and the neutral pictures picture category with group [F(3,153)=1.8]. The differ-
[F(1,153)=7.4, P<0.05]. Interestingly, the smoking cues ences between individual means of the control pictures
were similar to the pleasant and neutral ones. The differ- were significant [F(1,51) values ranging from 65.0 to
ence in the overall mean for the smoking cues and that of 483.4, all P<0.001]. Overall ratings for smoking pictures
the unpleasant control pictures was significant [Tukey's were higher than for aversive [F(1,51)=256.9, P<0.001]
HSD test, P<0.05]. and neutral control pictures [F(1,51)=4.4, P<0.05] and
The zygomatic muscle also showed an overall effect smaller than for pleasant control pictures [F(1,51)=35.6,
of the picture category [F(3,153)=3.7, P<0.02] and no P<0.001].
evidence of a group effect or interaction of category of The arousal ratings revealed a main effect of picture
picture with group [all F values <0.8]. However, this pa- category [F(3,153)=191.2, P<0.001; Fig. 4, bottom pan-
rameter did have a significant block effect [F(1,51)=9.4, el], but no effect of group [F(2,51)=1.3] or interaction of
P<0.004], suggesting a habituation of the zygomatic ac- group with picture category [F(3,153)=0.5]. The overall
tivity over the two blocks (see Fig. 3, bottom panel). mean for the smoking cues was smaller than for pleasant
More importantly, there was a suggestion of a significant and unpleasant control pictures, but larger than for neu-
interaction of block by picture category [F(3,153)=3.5, tral control pictures [all F values ranged from 19.2 to
P<0.03]. Thus, only in the first block was there a sugges- 467.1, P<0.01].
tion of a difference between the muscle activities of the
different individual categories of pictures and this was
only between the activity during unpleasant and pleasant
288

Fig. 5 Mean startle magnitude (A-D units) measured during


viewing of smoking and control pictures (for details see Fig. 2)
during repeated testing of 18 never smokers in experiment 2

Experiment 2: effects of cues in never smokers


Fig. 4 Mean momentary state of pleasure (upper panel) and
arousal (lower panel) during viewing of smoking and control pic-
Demographic characteristics of the subjects
tures used in experiment 1. For further details see Fig. 1, Fig. 2
and Fig. 3 The subjects had a mean lifetime consumption of
0.6±0.2 cigarettes. Their average age was 25.7±1.2
years.
Effect of baseline startle magnitude on cue-produced
modulation of ASR and several of its correlates
Startle reflex effects of the experimental pictures
In the two groups of subjects formed by a median split
into those with lower and higher magnitudes of the star- There was a main effect of category of picture
tle response, evaluation of the overall ASR to the differ- [F(3,51)=3.1, P<0.05] with the control pictures evoking
ent pictures failed to confirm any simple role of the a pattern similar to that seen in experiment 1 (compare
baseline startle magnitude in the cue modulation. There Fig. 5 with Fig. 3). The startle reactions evoked during
was no interaction of picture category and magnitude unpleasant pictures were larger than during pleasant ones
[F(3,156)=0.4], although there was the expected effect of [F(1,51)=7.7, P<0.01]. Comparisons with neutral pic-
category [F(3,156)=7.4, P<0.001]. It was further seen tures showed a nearly significant difference with regard
that the ASRs for the smoking cues in the respective to pleasant [F(1,51)=3.6, P<0.06] but nothing apprecia-
groups with the high and low startle magnitudes ble with regard to unpleasant pictures [F(1,51)=0.7].
(67.9±3.7 and 27.8±1.9 A-D units) were signficantly However, with regard to the smoking pictures, the pat-
lower than those of the aversive control stimuli tern of effect seen in experiment 1 in the smokers was
(72.5±3.3 and 32.2±2.4 A-D units, Tukey HSD tests, not found in the present group of never smokers. The
P<0.05); however, for both high and low overall startle means for smoking cues and unpleasant control pictures
magnitudes, the respective ASRs of the positive stimuli was not significantly different [F(1,51)=0.1], as seen
(68.4±3.2 and 29.1±2.0 A-D units) were just slightly previously. Instead, there was an appreciable difference
higher than those of the smoking cues. between smoking cues and pleasant control pictures [Tu-
A corresponding evaluation of the subjective data for key's HSD test, P<0.05].
these two groups failed to find any effect of magnitude
of startle or its interaction for momentary pleasure or
arousal (all F values <1.2). There were also no apprecia- Pleasure and arousal evoked by experimental pictures
ble differences between the groups for the FTQ (t=0.9)
or years of smoking (both t values <1.5), but from the As found for the startle data, the pattern of the pictures
data on age there was a suggestion that the persons with on momentary pleasure was similar to that of experiment
lower startle magnitudes (26.5±1.2 years) as opposed to 1 for the control pictures but not for the smoking pic-
those with longer startles (23.4±0.9 years) were signifi- tures. Whereas in experiment 1 the smoking pictures
cantly older [t(52)=2.04, P<0.05]. were generally similar to the pleasurable ones, the smok-
ing pictures in experiment 2 were found here to lie be-
tween unpleasant and neutral material (compare upper
panel of Fig. 6 with that of Fig. 4). The smoking pictures
289

tures had a generally similar pattern of effect in both the


smokers and the never smokers. The effects of the smok-
ing pictures in the smokers were not affected by different
states of smoking withdrawal, smoke repletion and ex-
pectancy of smoking. This indicated that the effects of the
smoking cues were general to different test conditions.
By measuring ASR and facial EMG during presenta-
tion of smoking cues and control material, we also tested
the motivational effects of the cues with physiological
indices of motivation. The control scenes confirmed in
subjects selected for their smoking histories that differ-
ent motivational valences can be detected (see Introduc-
tion). Against these within-experiment reference points,
it was generally seen that smoking cues affected the
physiological measures in smokers as if they were pleas-
ant. This was most clear for the ASR (see Fig. 2 and
Fig. 5). Data consistent with this were also collected for
corrugator activity (see Fig. 3, upper panel). For zygo-
matic activity, there may have been a habituation effect
as only the first block of testing detected motivational
valence. Nevertheless, the data of this block were in line
Fig. 6 Mean subjective ratings of momentary pleasure (upper with the first two measures in that there was no clear evi-
panel) and arousal (lower panel) during viewing of smoking and dence that smoking cues were less pleasant than pleasant
control pictures in never smokers in experiment 2. For further de- control slides (see Fig. 3, lower panel).
tails see Fig. 4 and Fig. 5
It is important that this pattern of cue modulation ap-
peared to be specific to the smokers. Thus, relative to the
control slides, the smoking pictures influenced the ASR
evoked less pleasure than neutral and pleasant control in never smokers in exactly the opposite way to that seen
pictures but more pleasure than unpleasant control pic- in smokers; the startle responses were significantly higher
tures. There were significant differences among all the than the pleasant control pictures and similar to negative
individual means in the upper panel of Fig. 6 [all F val- ones. Nevertheless, it could be pointed out from Fig. 2
ues range from 10.4 to 182.7, all P<0.01]. and Fig. 5 that the overall startle magnitude differed in
All ratings of arousal tended to be similar to those of the two populations of subjects, and baseline differences
experiment 1 (compare lower panel Fig. 6 with that of could make comparisons of the smokers and never smok-
Fig. 4) except that the arousal ratings of the pleasant ers difficult. However, Bradley et al. (1993) showed that
control material was significantly less that that of the un- modulation of startle magnitude by pictures similar to our
pleasant control pictures. Accordingly, arousal for the non-drug control pictures was independent of differences
smoking pictures fell in the range of the pleasant control in the baseline startle magnitude produced by a habitua-
pictures. Except for the difference between smoking cues tion manipulation. We further showed in experiment 1
and pleasant control pictures [F(1,51)=0.4], all compari- that the modulation of startle produced by smoking cues
sons showed significant differences [F values ranged relative to non-smoking control pictures also occurs in
from 10.6 to 100.2, all P<0.01]. smokers having overall startle responses that are low. It is
therefore safe to suggest that the relative changes in the
startle response produced by smoking cues in smokers are
Discussion not simply a pattern of effects that would occur in any
population. The fact that our test population comprised
The present study addressed the mechanisms of drug cue persons without any experience with smoking is also con-
conditioning in humans. We replicated and extended ob- sistent with the idea that the pictures of smoking in smok-
servations that smoking cues may be appetitive rather ers are cues created by conditioning.
than aversive as traditionally believed (see Introduction). Lang and coworkers (Lang et al. 1990; Lang 1995)
The smoking cues were pictures of the preparation of argued from data on pictures similar to our control mate-
and/or actual smoking and as seen previously evoked rial that motivational valence modulates ASR and the fa-
strong desire for a cigarette (see Introduction). By com- cial EMG responses: pleasant and unpleasant pictures
paring these smoking pictures to pleasant, neutral or un- likely have approach and avoidance properties, respec-
pleasant control pictures, it was confirmed in dependent tively. Since drug cues tend to produce physiological
smokers that the cues appeared to be pleasant (see. arousal (Carter and Tiffany 1999), it needs to be empha-
Fig. 4b). Individuals without any experience with smok- sized that arousal was specifically shown not to account
ing found the same smoking pictures unpleasant (see for the modulation of ASR (Lang et al. 1990; Lang 1995;
Fig. 6). This contrasted with the fact that the control pic- Witvliet and Vrana 1995). Our data also fail to indicate a
290

simple relation between arousal and the modulation of tests for drug cues (Mucha 1991). In humans, drug avail-
the ASR by smoking pictures. Both smokers and never ability influenced cue effects on smoking behavior in
smokers showed clear differences in cue-modulated star- smokers (Droungas et al. 1995) and on physiological re-
tle responses despite comparable arousal ratings. There- sponses in alcohol drinkers (Turkkan et al. 1989). In ad-
fore, the present data also offer good support for smok- dition, important internal states such as deprivation need
ing cues being appetitive and encoding cue approach. to be addressed as modifiers of incentive responses to
Traditional pharmacological/adaptive theories of drug cues (see Toates 1994). The fact that analogous manipu-
cues hold that the cues evoke conditioned reactions simi- lations were not effective in the present study would sug-
lar to withdrawal; they are therefore assumed to be aver- gest that physiological tests like the startle test are partic-
sive (see Introduction). Motivation for drug intake would ularly useful in teasing apart underlying motivational
then be reinforced negatively through alleviation of dis- processes from their situationally-specific expression.
comfort. From the absence of any aversive effects of the This would be important in clinical situations where con-
pictures of smoking on both subjective and physiological trol during testing is difficult. A consideration of goal
measures in humans, we would conclude that the effects characteristics could account for data of a previous study
of our cues are not accounted for by these theories. analogous to the present that looked at imageries as cues.
In order to integrate the extensive support for these no- These cues were evoked by a tone, but they evoked aver-
tions (see Siegel 1989; Poulos and Cappell 1991; Ramsey sive effects (Elash et al. 1995). Whereas this is clearly at
and Woods 1997) with the present data, there are several odds with the present observations, bringing the imager-
points: First, we would indicate that the relevant support for ies under control of the tone required considerable expo-
the traditional theories come from compensatory response sure of the subjects to the cues. It may be suggested that
conditioning, which is largely based on non-motivational experience with a cue may reverse the motivational va-
measures in animals. Whereas the data do not conflict with lence of the cue, as indicated from repeated self-injection
one another, it still remains to be determined how the condi- of placebo in opiate addicts (O'Brien et al. 1986).
tioned physiological effects account for craving produced Finally, features of the present startle test may be used
by drug cues. In the human, experimentally-produced to address differences among various incentive motivation-
smoking cues evoke physiological responses, but they ap- al theories of cues. The original theory of Stewart et al.
pear to serve preparatory/appetitive functions (Mucha et al. (1984) would predict a pattern of effects similar to our re-
1998). Second, one could argue that aversive effects were sults. They would suggest that cues be pleasant. However,
present, but they were not detected. The pattern of effects the theory of Robinson and Berridge (1993) would not. In-
noted here also make this unlikely. Moreover, the present deed, they cite secondary evidence that smoking cues be
startle test is particularly sensitive to aversive effects unpleasant in dependent smokers (p. 253), which was not
(Patrick et al. 1996; Koch and Schnitzler 1997; Fendt and borne out by our findings. Whereas other features of the
Fanselow 1999). Finally, one could suggest that smokers Robinson and Berridge model are intriguing, many of their
are not a good model of drug cues, as the traditional phar- points about subjective effects of drugs and drug cues may
macological/adaptive theories are largely based on sub- need direct examination with procedures like the present.
stances other than nicotine. Indeed, motivational effects of
smoking and nicotine withdrawal do not appear to meet the Acknowledgements The work was funded by the Deutsche
expectations of a classic substance of abuse (Mucha 1997; Forschungsgemeinschaft (Mu 1136/2-2). Acknowledged are the fol-
lowing individuals for help in collecting the data: Anja Müller, An-
Müller et al. 1998, Mucha et al. 1999). Similarly, in experi- drea Dolfen and Markus Weber. The authors are also very thankful
ment 1, acute smoking deprivation increased desire for a to Professors Niels Birbaumer and Karl Mann for support during
cigarette without being accompanied by any consistent un- various phases of this work and to Dr. Oliver Diedrich for helpful
pleasant effect of the acute withdrawal on either subjective discussions and programming assistance. The work was also made
in part possible by a generous loan of a sound generator from C.
or physiological tests. However, the appetitive nature of Wolk and Professor M. Velden (Osnabrück) and a Smokerlyzer
cues may not be limited to smoking cues or to the use of an from Professor E. Stephan (Köln), respectively. In addition, R. F. M.
acute test such as the present. Alcohol cues also failed to is supported by the BMBF Addiction Research Center in Tubingen.
show aversive effects in social drinkers (Mucha et al 1999) Part of the data was reported previously (Geier et al. 1998).
and recent data suggest that this is also the case in alcohol-
ics in treatment (Mucha et al. 2000).
Therefore, the present observations may be most References
fruitfully explained by incentive motivational theories.
These notions see drug-paired stimuli as appetitive, elic- Altman J, Everitt BJ, Glautier S. Markou A, Nutt D, Oretti R,
iting approach and preparatory responses (see Introduc- Phillips GD, Robbins TW (1996) The biological, social and
clinical bases of drug addiction: commentary and debate. Psy-
tion). The main implication is that the mechanism of the chopharmacology 125:285–345
cue formation lies within the defined reinforcement Bradley MM, Lang PJ, Cuthbert BN (1993) Emotion, novelty, and
system in the brain (Stewart et al. 1984; Wise 1987). the startle reflex: habituation in humans. Behav Neurosci
However, there are a number of general features of in- 107:970–980
Bushnell PJ, Levin ED, Marrocco RT, Sarter MF, Strupp BJ,
centive motivational processes that may now need con- Warburton DM (2000) Attention as a target of intoxication: in-
sideration in human work on drug cues. One of the few sights and methods from studies of drug abuse. Neurotoxicol
that has been examined concerns goal characteristics of Teratol (in press)
291
Carter BL, Tiffany ST (1999) Meta-analysis of cue reactivity in Mucha RF (1997) Preference for tastes paired with a nicotine an-
addiction research. Addiction 94:327–340 tagonist in rats chronically treated with nicotine. Pharmacol
Della Casa V, Hofer I, Weiner I, Feldon J (1998) The effects of Biochem Behav 56:175–179
smoking on acoustic prepulse inhibition in healthy men and Mucha RF, Pauli P, Angrilli A (1998) Conditioned responses elic-
women. Psychopharmacology 137:362–268 ited by experimentally produced cues for smoking. Can J
Droungas A, Ehrman RN, Childress AR, O'Brien CP (1995) Effect Physiol Pharmacol 76:259–268
of smoking cues and cigarette availability on craving and Mucha RF, Geier A, Pauli P (1999) Modulation of craving by cues
smoking behavior. Addict Behav 20:657–673 having differential overlap with pharmacological effect: evi-
Drummond DC, Cooper T, Glautier SP (1990) Conditioned learn- dence for cue approach in smokers and social drinkers. Psy-
ing in alcohol dependence: implications for cue exposure chopharmacology 147:306–313
treatment. Br J Addict 85:725–743 Mucha RF, Geier A, Stuhlinger M, Mundle G (2000) Appetitive
Elash CA, Tiffany ST, Vrana SR (1995) Manipulation of smoking effects of drug cues modelled by pictures of the intake ritual:
urges and affect through a brief-imagery procedure: self-re- generality of cue-modulated startle examined with inpatient al-
port, psychophysiological, and startle probe responses. Exp coholics (in press)
Clin Psychopharmacol 3:156–162 Müller V, Mucha RF, Pauli P (1998) Dependence on smoking and
Epstein LH, Perkins KA, Jennings JR, Pastor S (1990) Effects of the acoustic startle response in healthy smokers. Pharmacol
smoking context on habituation to a repeated cognitive task. Biochem Behav 59:1031–1038
Psychopharmacology 100:366–371 Nader K, Bechara A, van der Kooy D (1997) Neurobiological con-
Fagerström KO (1978) Measuring degree of physical dependence straints on behavioral models of motivation. Annu Rev Psy-
to tobacco smoking with reference to individualization of chol 48:85–114
treatment. Addict Behav 3:235–241 Nesse RM, Berridge KC (1997) Psychoactive drug use in evolu-
Fendt M, Fanselow MS (1999) The neuroanatomical and neuro- tionary perspective. Science 278:63–66
chemical basis of conditioned fear. Neurosci Biobehav Rev O'Brien CP, Ehrman RN, Ternes JW (1986) Classical conditioning
23:743–760 in human opioid dependence. In: Goldberg SR, Stolerman IP
Geier A, Mucha RF, Diedrich O, Pauli P, Müller V (1998) Motiva- (eds) Behavioral analysis of drug dependence. Academic
tional effects of nicotine withdrawal examined with the poten- Press, Orlando, pp 329–356
tiated acoustic startle response in healthy smokers. Eur J Neu- O'Brien CP, Childress AR, Mclellan AT, Ehrman RN (1992) A
rosci Suppl 10:311 learning model of addiction. Res Publ Assoc Res Nerv Ment
Hagemann D, Naumann E, Becker G, Maier S, Bartussek D Dis 70:157–177
(1998) Frontal brain asymmetry and affective style: a concep- Patrick CJ, Berthot BD, Moore JD (1996) Diazepam blocks fear-
tual replication. Psychophysiology 35:372–388 potentiated startle in humans. J Abnorm Psychol 105:89–96
Hamm AO, Cuthbert BN, Globisch J, Vaitl D (1997) Fear and the Poulos CX, Cappell H (1991) Homeostatic theory of drug toler-
startle reflex: blink modulation and autonomic response pat- ance: a general model of physiological adaptation. Psychol
terns in animal and mutilation fearful subjects. Psychophysiol- Rev 95:390–408
ogy 34:97–107 Ramsey DS, Woods SC (1997) Biological consequences of drug
Kirk RE (1995) Experimental design: procedures for the behavior- administration: implications for acute and chronic tolerance.
al sciences, 3rd edn. Brooks/Cole, Pacific Grove Psychol Rev 104:170–193
Koch M, Schnitzler H-U (1997) The acoustic startle response in Robinson TE, Berridge KC (1993) The neural basis of drug crav-
rats – circuits mediating evocation, inhibition and potentiation. ing an incentive-sensitization theory of addiction. Brain Res
Behav Brain Res 89:35–49 Rev 18:247–291
Kolb L, Himmelsbach CK (1938) Clinical studies of drug addic- Siegel S (1975) Evidence from rats that morphine tolerance is a
tion. III. A critical review of the withdrawal treatments with learned response. J Comp Physiol Psychol 89:498–506
method of evaluating abstinence syndromes. Am J Psychiatry Siegel S (1989) Pharmacological conditioning and drug effects.
94:759–799 In: Goudie AJ, Emmett-Ogglesby MW (eds) Psychoactive
Koob GF, Caine SB, Parsons L, Markou A, Weiss F (1997) Oppo- drugs: tolerance and sensitization. Humana Press, Clifton,
nent process model and psychostimulant addiction. Pharmacol N.J., pp 115–180
Biochem Behav 57:513–521 Sobell LC, Sobell MB (1990) Self-reports across addictive behav-
Kumari V, Checkley SA, Gray JA (1996) Effect of cigarette smok- iors: issues and future directions in clinical settings. Behav
ing on prepulse inhibition of the acoustic startle reflex in heal- Assess 12:1–4
thy male smokers. Psychopharmacology 128:54–60 Solomon RL, Corbit JD (1974) An opponent-process theory of
Lamb RJ, Preston KL, Schindler C, Meisch RA, Davis F, Katz JL, motivation: I. Temporal dynamics of affect. Psychol Rev
Henningfield JE, Goldberg SR (1991) The reinforcing and 81:119–145
subjective effects of morphine in post-addicts: a dose-response Stewart J, de Wit H, Eikelboom R (1984) Role of unconditioned
study. J Pharmacol Exp Ther 259:1165–1173 and conditioned drug effects in the self-administration of opi-
Lang PJ (1995) The emotion probe. Studies of motivation and at- ates and stimulants. Psychol Rev 91:251–268
tention. Am Psychol 50:372–385 Toates F (1994) Comparing motivational systems – an incentive
Lang PJ, Bradley MM, Cuthbert BN (1990) Emotion, attention, motivation perspective. In: Legg CR, Booth DA (eds) Appe-
and the startle reflex. Psychol Rev 97:337–395 tite: neural and behavioural bases. Oxford University Press,
Lang, PJ, Greenwald MK, Bradley MM, Hamm AO (1993). Look- Oxford, pp 305–327
ing at pictures: affective, facial, visceral, and behavioral reac- Turkkan JS, McCaul ME, Stitzer ML (1989) Psychophysiological
tions. Psychophysiology 30:261–273 effects of alcohol-related stimuli: II. Enhancement with alco-
Lazev AB, Herzog TA, Brandon TH (1999) Classical conditioning hol availability. Alcohol Clin Exp Res 13:392–398
of experimental cues to cigarette smoking. Exp Clin Psycho- Wikler A (1973) Dynamics of drug dependence: implications of a
pharmacol 7:56–63 conditioning theory for research and treatment. Arch Gen Psy-
McDermut W, Haaga DAF (1998) Effect of stage of change on chiatry 28:611–616
cue reactivity in continuing smokers. Exp Clin Psychopharma- Wise RA (1987) The role of reward pathways in the development
col 6:316–324 of drug dependence. Pharmacol Ther 35:227–263
Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF Witvliet CV, Vrana SR (1995) Psychophysiological responses as
(1993) Animal models of drug craving. Psychopharmacology indices of affective dimensions. Psychophysiology 32:436–
112:163–182 443
Mucha RF (1991) What is learned during opiate withdrawal con- Zinser MC, Fiore MC, Davidson RJ, Baker TB (1999). Manipulat-
ditioning? Evidence for a cue avoidance model. Psychophar- ing smoking motivation: impact on an electrophysiological in-
macology 104:391–396 dex of approach motivation. J Abnorm Psychol 108:240–254

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