Alcohol and Alcoholism Advance Access originally published online on January 24, 2008
Alcohol and Alcoholism 2008 43(2):151-162; doi:10.1093/alcalc/agm179
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Effects of stress on emotional reactivity in hostile heavy social drinkers following dietary tryptophan enhancement
Department of Psychology, University of Sussex, Falmer, Brighton, UK
* Author to whom correspondence should be addressed: Tel.: +44 1273 678 879; Fax: +44 1273 678058; E-mail: t.duka{at}sussex.ac.uk
Received 13 February 2007; first review notified 20 April 2007; in revised form 5 December 2007; accepted 12 December 2007
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ABSTRACT |
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Aim: Because individuals high on hostility may be at risk for alcohol abuse due to serotonergic dysfunction and greater reactivity to stress, we examined the effects of acute dietary tryptophan enhancement and stress on mood and craving for alcohol in low-hostile (LoH) and high-hostile (HiH) individuals. Methods: Thirty-four LoH and 33 HiH heavy social drinkers [selection based on the Hostility scale from the Buss and Perry Aggression Questionnaire (1992)] received either tryptophan-enriched or control diet and underwent a stress-induction procedure. Trait differences between the two hostile groups were explored using personality, anxiety, and depression questionnaires. Mood, craving for alcohol, and salivary cortisol levels (CORT) were measured before and after tryptophan and after stress-induction. Heart rate (HR) was measured during stress-induction. Results: HiHs compared to LoHs scored higher on the depression and anxiety trait scales as well in the character dimension Harm Avoidance and reported more of stress exposure over the past month. They also showed more negative mood and higher craving for alcohol. Diet alone did not produce any subjective or physiological effects. Stress increased CORT, HR, negative mood, and craving for alcohol. HiHs displayed higher CORT increase and lower cardiovascular reactivity in response to stress compared to LoHs. Opposite to the predictions, tryptophan enhancement selectively facilitated stress-induced increase in craving in the HiHs. Conclusion: Among heavy drinkers HiHs report higher craving for alcohol and show greater reactivity to stress as measured by CORT and negative mood. The effects of stress on craving in HiHs may be mediated by a serotonergic mechanism.
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Introduction |
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Stress is considered to be an important factor in the initiation, maintenance, and relapse to alcohol abuse (Brady and Sonne, 1999
; Brown et al., 1990; Lê and Shaham, 2002; Marlatt, 1979; Pohorecky, 1991; Wolffgramm and Heyne, 1991). Human laboratory studies have supported a strong positive relationship between experimentally induced stress and alcohol-related behaviors. Stressors increase alcohol craving and subjective anxiety and induce autonomic changes (Coffey et al., 2002; Cooney et al., 1997; Nesic and Duka, 2006; Sinha and O’Malley, 1999) and a number of studies have demonstrated an increase in alcohol consumption following acute stress in social drinkers (de Wit et al., 2003; Higgins and Marlatt, 1975; Nesic and Duka, 2006; Pelham et al., 1997) and alcoholics (Miller et al., 1974).
It has been suggested that stress activates the brain reward circuits thus increasing their sensitivity to the positively reinforcing properties of drugs leading to increased motivation to use drugs (Piazza and Le Moal, 1997, 1998). Animal studies have shown that stress primes drug-related behaviors via stimulation of the mesolimbic dopamine (incentive) system by glucocorticoids (Piazza and Le Moal, 1997, 1998; Fahlke et al., 1994a, 1994b, 1995).
Although activation of the mesolimbic dopamine (DA) system is thought to underlie drug- and cue-induced priming (Stewart et al., 1984), there is evidence to suggest that other neurotransmitter systems may contribute to stress-induced priming (Lê and Shaham, 2002; Liu and Weiss, 2002; Stewart, 2000, 2003). For instance, stress-induced reinstatement of alcohol-seeking in rats was blocked by the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor fluoxetine, and not by naltrexone, a drug that is known to block opioid-induced activation of the mesolimbic DA system (Lê et al., 1999). Intraraphe infusions of corticotropin-releasing factor (CRF) have been found to suppress 5-HT cell firing and release (Kirby et al., 2000; Lê et al., 2002). This effect of CRF is thought to underlie stress-induced reinstatement of alcohol-seeking because suppression of 5-HT release produced by intraraphe infusion of 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], a 5-HT1A agonist, was also found to reinstate alcohol seeking in rats (Lê et al., 2002). These findings taken together suggest that the effects of stress on alcohol-related behaviors may be associated with 5-HT function.
The involvement of 5-HT in stress-induced alcohol-related behaviors is particularly interesting in view of the proposals that reduced serotonergic function may contribute to the development of alcoholism (Ballenger et al., 1979). More recent findings from genomic studies have also demonstrated a causal link between 5-HT transporter promoter (5-HTTLPR) polymorphism and susceptibility to alcoholism (Hu et al., 2005). Despite certain inconsistencies in the literature (see LeMarquand et al., 1994, for a review), the review by Naranjo, Chu and Tremblay (2002) concluded that serotonergic dysfunction may indeed contribute to the development of alcohol dependence via impaired impulse control and/or mood regulation. Moreover, van Praag (1998) has suggested that serotonergic disturbance may increase individuals’ susceptibility to stress. In confirmation of this hypothesis, Higley and Bennett (1999) have noted that excessive alcohol consumption in individual nonhuman primates who are characterized by a serotonergic deficit may be particularly evident in stressful conditions. It could thus be postulated that reduced serotonergic function may predispose individuals to alcohol-related behaviors in stressful circumstances.
Hostility trait has been linked to reduced 5-HT function (Manuck et al., 1998; Møller et al., 1996). If hostile individuals have reduced 5-HT function, then they should be more susceptible to the effects of stress. Indeed, compared to low hostile, high-hostile individuals report more of anger in response to provocation (Felsten and Hill, 1999), show enhanced and prolonged cardiovascular, noradrenaline, testosterone, and cortisol responses to verbal harassment (Suarez et al., 1998), as well as greater increase in blood pressure in response to a public speaking stressor (Fichera and Andreassi, 2000) and a stressful discussion (Smith and Gallo, 1999). Greater vulnerability of high-hostile individuals to stress is particularly interesting in view of the possibility that hostility predisposes individuals to alcohol abuse (Gerra et al., 1999).
The aims of this experiment are twofold. First, it was designed to explore the personality profile of the hostile population (identified according to the Hostility scale of the Aggression Questionnaire [AQ; Buss and Perry 1992]) and their reactivity to stress and susceptibility to alcohol-related behavior. This was accomplished using several trait and state questionnaires, including Beck's Depression Inventory (BDI; Beck, 1987), State-Trait Anxiety Questionnaire (STAI; Spielberger et al., 1990), Temperament and Character Inventory (TCI; Cloninger et al., 1994), and Perceived Stress Scale (PSS; Cohen et al., 1983), in addition to scales measuring current mood and craving for alcohol, before and after stress induction.
Second, using a dietary tryptophan enhancement method (based on Markus et al., 2000a), the experiment set out to explore the involvement of serotonergic transmission in mediating the incentive value of alcohol (expressed as subjective craving for alcohol) before and after stress-induction. Dietary tryptophan manipulations are based on the fact that influx of tryptophan into the brain, which is determined by its ratio to the sum of other competing large neutral amino acids (LNAA), is the only rate-limiting factor of 5-HT synthesis (Wurtman et al., 1981). The dietary method of tryptophan enhancement using carbohydrate-rich food with the addition of 
-lactalbumin, a whey protein with very high tryptophan content (7%; Denness and Patten, 1959), has been chosen for two reasons. First, alterations in tryptophan/LNAA ratio achieved by this method are modest and within physiological range—less than 50% increase relative to the control diet (Markus et al. 2000a; Nesic et al. 2003). This fact is very important since large doses of tryptophan that elevate brain tryptophan levels beyond the physiological range have been found to slow the firing of 5-HT neurones and may thus diminish 5-HT release and/or suppress 5-HT synthesis (Wurtman et al., 1981). Second, this method was chosen in view of the possibility that susceptibility to alcoholism and stress may be ameliorated with the appropriate dietary intervention that could be applied in primary clinical settings, thus overcoming ethical problems of preventative pharmacological intervention in vulnerable heavy social drinkers.
Tryptophan manipulations—both enhancement and depletion—appear to produce behavioral effects in individuals who already suffer from a 5-HT dysfunction, such as those prone to depression (Delgado et al., 1990; Young et al., 1985) and those with greater hostility and aggression (Bjork et al., 2000; Cleare and Bond, 1994, 1995; Dougherty et al., 1999; Finn et al., 1998). Furthermore, individuals who have been exposed to stress in recent past have greater susceptibility to tryptophan-induced behavioral changes (Markus et al., 1998). In addition, since 5-HT neurones fire at higher rates when an organism is aroused or stressed (Jacobs and Fornal, 1999), it has been postulated that tryptophan manipulations may exert a greater effect under arousing conditions (Young et al., 1988), which include certain degree of provocation (Bjork et al., 1999).
It was hypothesized that high-hostile individuals, who may suffer from serotonergic dysregulation (Manuck et al., 1998; Møller et al., 1996) and be more reactive to stress (Felsten and Hill, 1999; Fichera and Andreassi, 2000; Smith and Gallo, 1999; Suarez et al., 1998), would display greater increase in their craving for alcohol and show greater physiological and emotional reactivity in stressful situation compared to the low-hostile individuals. Furthermore, it was hypothesized that modulation of serotonergic function using dietary tryptophan enhancement may not produce behavioral effects in the absence of stress but that it would reduce the subjective and physiological stress response particularly in high-hostile individuals. The latter prediction was in line with the findings by Markus and colleagues (2000a, 2000b, 1998) that tryptophan enhancement selectively reduces the effects of stress in high- but not low-stress-prone participants.
The stress-induction method employed here is based on the Trier Social Stress Test (TSST; Kirschbaum et al., 1993), a procedure which was found to reliably produce a physiological response in experimental volunteers (cortisol, heart rate, ACTH; Kirschbaum et al., 1993, 1995). We have previously found this procedure to be effective in modulating mood, cortisol levels, skin conductance response as well as alcohol consumption in heavy social drinkers (Nesic and Duka, 2006).
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Methods |
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Participants
Sixty-seven moderate-to-heavy social drinkers aged 18–32 (mean = 21.04, SE = 0.36) consuming on average 21.90–101.13 alcohol units per week (mean = 37.48, SE = 2.06) took part in this experiment.
Thirty-four individuals were recruited as low hostile (LoH; 13 male, 21 female; hostility scores <18 and <16.5, respectively) and 33 as high hostile (HiH; 12 male, 21 female; hostility scores >18 and >16.5, respectively) [Hostility subscale scores from the Aggression Questionnaire (AQ; Buss and Perry, 1992)]. The subjects were preselected on the basis of these cutoff points, which represent median values for males and females from the sample of 388 volunteers from the Experimental Psychology participant pool who had previously completed the AQ. The groups could not be exactly matched for gender due to the difficulties with recruitment of HiH males. Therefore the groups were counterbalanced with the male–female ratio being approximately 0.61.
Participants were recruited via the Experimental Psychology participant pool and were mostly students at the University of Sussex. Participants were only permitted to take part in this study if they were between 18 and 40 years of age and if they consumed 21 or more alcohol units per week (the maximum recommended weekly alcohol intake for men; Department of Health, 1992), as reported in the general recruitment questionnaire. All individuals who applied to take part in this experiment completed a detailed health questionnaire administered by a medical doctor and those with physical and psychiatric conditions that might be adversely affected by the experimental procedure or that might affect the outcome of the experiment were not permitted to take part. Participants were thus generally in good physical and mental health, were not taking any medication other than the contraceptive pills, and their weights were within 15% of the normal weight limit for their heights. Participants were also screened for their smoking habits and were given a score on a scale with 0 = I do not smoke to 1 = I light a cigarette every 2 or more hours, 2 = every hour, 3 = every half hour, 4 = every 15 min and 5 = every 5 or 10 min. All participants gave their informed consent before taking part in this study and received payment at the end of the testing session. This study was approved by the University of Sussex Ethics Committee for the use of humans in compliance with the Declaration of Helsinki for human participants.
Experimental design
Participants were tested individually in a two-way (2 x 2) between-subjects design. Low- (LoH) and high-hostile (HiH) individuals (factor 1: hostility group) were randomly allocated either to tryptophan (TRP+) or to control (CTR) diet condition (factor 2: diet; diets were administered in a double-blind manner). The four experimental groups were balanced for gender and the time of testing (testing slot starting at 9.25 a.m. vs. 10.40 a.m.). Experimental time point was introduced as an additional within-subjects factor for several dependent measures.
The dependent variables were mood, craving for alcohol, salivary cortisol levels, and heart rate.
Experimental procedure
Prior to attending the testing session (not more than 7 days before), participants attended the laboratory where they gave their written consent to participate in the study designed to explore the effects of various activities on mood, attention, and perception of taste. Subjects then completed the AQ and AUQ and were then given a battery of questionnaires consisting of TCI, STAI, BDI, and PSS to complete at home and return to the experimenter at the beginning of the main testing session.
Participants were instructed to fast for at least 12 h before the main experimental session (only permitted water and tea without sugar and milk) and were told that compliance would be tested using saliva samples. They were also asked to abstain from drinking alcohol for 12 h, using illicit drugs for at least 3 days and taking sleeping pills and other sedatives for 48 h before the testing session and were told that breathalyser test and urine drug tests might be administered during the experimental session. This is the standard procedure used in our lab to ensure compliance with abstinence requirements and participants, expecting a urine test, occasionally report at the beginning of the session if they had not been abstaining and their session is subsequently rescheduled. While compliance with fasting instructions has not been verified in this study, results from our pilot study using this method revealed that volunteers generally tended to be compliant, as indicated by blood glucose levels at the beginning of the session (mean ± SEM: 95.13 ± 1.89 mg/dl). In addition to this, participants were instructed not to smoke and to avoid any strenuous physical activity for an hour before coming to the laboratory.
On the day of testing, participants arrived at the laboratory either at 9.25 a.m. or at 10.40 a.m. After the breathalyser test they were seated in the waiting room for about 10 min before being taken to the main experimental cubicle where they completed POMS, DAQ, and KUSTA questionnaires and gave a baseline saliva sample (t1). Participants were then instructed to return to the waiting room and the dietary manipulation started at 10.00/11.15 a.m. After breakfast, each subject was given a 500-ml bottle of water to consume ad lib throughout the testing session. Smokers were allowed to smoke immediately after breakfast, snacks, and lunch (if they wished to do so). After the end of the dietary manipulation (at 12.20/13.35 p.m.) participants were allowed to rest for approximately 1 h, after which they were given the heart rate monitoring equipment and asked to go to the toilet and fit the chest transmitter and then to return to the waiting room. Fifteen minutes later (at 13.35/14.50 p.m.) participants were taken to the main experimental cubicle where they completed POMS, DAQ, and KUSTA questionnaires and provided another saliva sample (t2). The stress induction started at 13.45/15.00 p.m. (1 h 25 min after the end of the dietary manipulation) and lasted approximately 23 min, after which participants again completed POMS, DAQ, and KUSTA and gave a sample of saliva (t3). Participants then performed a series of other tests (not reported here), after which they were debriefed about the purpose of the study, paid for their participation, and were allowed to leave the laboratory.
Stress induction
The stress-induction method developed by Nesic and Duka (2006) was used in this study. Initially, the participants were informed via standardized written instructions about the requirements of the procedure (2 min). Participants were required to prepare (8 min) and deliver a 5-min speech as part of a fictional job interview. Participants were informed that their presentation would be recorded and that it would later be analyzed by three independent observers for right or wrong (for the interview) nonverbal behavior. The speech outline written during the speech preparation period was not available to participants during the speech delivery. The participants had to perform the speech standing up in front of the experimenter (who was taking notes as they were speaking) and a video camera, and were instructed to look at themselves on the TV screen in order to be able to assess their performance afterwards. If participants finished their speech in less than 5 min, the experimenter waited for 15 s before prompting them to continue and, if participants stopped again before the 5 min were up, there was a pause of 20 s after which the experimenter asked standardized questions until the end of the 5-min period. Participants were then asked to write down what they thought was the best and the worst aspect of their performance (2 min). Another stressor was then introduced, a mental arithmetic task (serially subtracting number 7 from 1013 whilst keeping constant eye contact with the experimenter) for further 5 min. On every mistake participants were asked to start counting again from 1013. Whenever necessary during the task performance, the participants were reminded to keep eye contact or to count faster.
Diets
The tryptophan manipulation procedure developed by Markus et al. (2000a) was modified and tested in our laboratory. Ten participants received either tryptophan-rich (TRP+) or control (CTR) diet administered in a double-blind manner. Blood samples were taken at baseline and 90 min after lunch and subsequently analyzed using fluorometry for tryptophan (as described by Badawy and Evans, 1976) and standard amino acid autoanalyzer procedure (for other LNAA). Compared to baseline, TRP+ diet produced an increase in the serum tryptophan/LNAA ratio by an average of 29.01%, while the CTR diet tended to reduce the ratio by 15.29% (Nesic et al., 2003).
The meal composition and composition of experimental drinks for each diet group as well as the time line of the dietary manipulation are presented in Tables 1 and 2. The hot chocolate drinks were served 10 min before the start of the meals (breakfast and lunch).
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Physiological measurements
Salivary cortisol. Saliva samples were collected using Salivettes (Sarstedt). Participants were instructed to place the cotton swab in their mouth and chew on it gently for 2 min. The participants then replaced the swab into the Salivette, which was sealed and stored in a freezer at –20°C until analysis using DELFIA assays (Wood et al., 1997
). To minimize variability in cortisol levels, cortisol data were presented and analyzed in terms of percentage change (prestress changes: levels at t2 expressed as percentage of t1 levels; stress-induced changes: t3 levels expressed as percentage of t2 levels). Heart rate. Heart rate was measured using Polar S610 heart rate monitor. The measurements were taken continuously at 5-s intervals throughout the stress-inducing procedure (between the time points t2 and t3). For the purposes of statistical analyses, mean heart rate was calculated for the 30-s baseline period as well as for each of the three stages of the stressful procedure (preparation, speech, mental arithmetic).
Blood alcohol level (BAL). BAL was measured using Lion Alcolmeter at the beginning of the testing session to ensure compliance with the abstinence requirement of the study. Individuals whose BAL was above 0% were not allowed to participate in the study.
Subjective measurements
The Alcohol Use Questionnaire (AUQ) (Mehrabian and Russell, 1978) is a self-report questionnaire, which establishes the average weekly alcohol intake over a 6-month period and with information about patterns of drinking that constitutes a binge drinking score.
The Aggression Questionnaire (AQ) (Buss and Perry, 1992) consists of 29 statements and participants are required to mark how much each statement applies to them on a scale of 1 ("extremely uncharacteristic of me") to 5 ("extremely characteristic of me"). These items load onto four different factors: Physical Aggression, Verbal Aggression, Anger, and Hostility.
The Profile of Mood States (POMS) (McNair et al., 1971) is a list of 72 mood-related adjectives, which are rated on a 5-point scale, ranging from "not at all" [0] to "extremely" [4]. These items are grouped into eight basic factors (Anxiety, Depression, Anger, Vigor, Fatigue, Confusion, Friendliness, and Elation) as well as two composite scores, Arousal [(Anxiety + Vigor) – (Fatigue + Confusion)] and Positive Mood (Elation – Depression).
KUSTA (Binz and Wendt, 1990; Wendt et al., 1985) consists of three 17-point bipolar scales (Mood, Activity, Tension/Relaxation) and three 17-point scales ranging from "not at all" [1] to "extremely strong" [17] (Happiness, Anxiety, and Anger).
The Desire for Alcohol Questionnaire (DAQ) (Love et al., 1998) is a 14-item questionnaire which measures four different aspects of craving for alcohol: Mild Desire, Strong Desire with Intention to Drink, Negative Reinforcement, and Loss of Control over alcohol use. The participants are required to rate how much each statement applies to them at that particular moment by writing a mark on a Likert-type 7-point scale, ranging from "strongly disagree" [1] to "strongly agree" [7]. For the purpose of this article, however, only the effects on the total craving score (sum of the four factor scores) will be reported.
The Temperament and Character Inventory (TCI) (Cloninger et al., 1994) is a self-report questionnaire consisting of 240 statements, each rated on a 2-point scale ("True" vs. "False"). The questionnaire assesses four dimensions of temperament [Harm Avoidance (HA), Novelty Seeking (NS), Reward Dependence (RD), and Persistence (P)] and three dimensions of character [Self-directedness (SD), Co-operativeness (C), and Self-transcendence (ST)].
The State-Trait Anxiety Inventory (STAI), trait version, (Spielberger et al., 1990) is a 20-item questionnaire, which measures the construct of general anxiety. Participants indicate on a scale of 1– 4 whether each statement describes what they generally feel (1 = almost never, 4 = almost always).
The Beck Depression Inventory (BDI) (Beck, 1987) consists of 21 items, each containing four statements. The participants are instructed to circle one or more of the statements in each item of the questionnaire, which best describe how they have been feeling during the past week. The depression score is calculated by adding up the maximal score from each item (range 0–4).
The Perceived Stress Scale (PSS) (Cohen et al., 1983) is a 10-item inventory that measures the degree of stress individuals have been exposed to over the past month and their subjective experience of stressful events. Participants are required to indicate on a scale from 0–4 how frequently they felt or thought in a certain way (0 = never, 4 = very often).
Statistical analyses
Differences in demographic characteristics between the four experimental groups were analyzed by univariate ANOVAs, with diet (TRP+ vs. CTR) and hostility groups (LoH vs. HiH) as between-subject factors. Personality differences between the two hostility groups were examined with a series of independent-sample t-tests.
Cortisol data were analyzed separately for the effects of diet alone (t1–t2) and diet in combination with stress (t2–t3) using univariate ANOVAs, with diet and hostility groups as between-subject factors. Cortisol levels at baseline (t1) were also analyzed using univariate ANOVA, for any differences between diet groups and hostility groups. In addition to this, in order to evaluate the significance of changes in cortisol levels both prior to and after stress induction, one-sample t-tests (from 0) were performed on the data from the entire experimental sample.
Average heart rate was analyzed using a three-way mixed ANOVA with phase of the stress manipulation (baseline vs. instruction/preparation vs. speech vs. mental arithmetic) as the within-subject factor and diet and hostility groups as the between-subjects factors.
Mood and craving data were analyzed separately for the effects of diet alone (t1–t2) and diet in combination with stress (t2–t3) using three-way mixed ANOVAs, with diet group (TRP+ vs. CTR) and hostility group (LoH vs. HiH) as between-subject factors and time point (t1 vs. t2 or t2 vs. t3) as the within-subject factor.
Holme's correction was applied in order to reduce the increased likelihood of family-wise type 1 error when a series of three or more comparisons was performed, such as several ANOVAs of related factors (e.g., POMS and KUSTA factors). The adjusted significance level (') was calculated by dividing the standard significance level ( = 0.05) by the number of comparisons performed (c): ' = /c.
Significant two-way interactions were explored with a series of independent- and paired-sample t-tests as well as one-sample t-tests (if applicable).
All analyses were performed using SPSS 9.0 software.
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Results |
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Population characteristics
Demographic characteristics of LoH and HiH individuals allocated to the two diet groups are presented in Table 3. The four experimental groups were matched for age as well as level and history of alcohol use. No significant differences between the groups were observed with respect to illicit drug use (data not shown). However, an interaction between diet and hostility group was found with respect to the level of daytime smoking (F[1,63] = 6.581, P < 0.05). Subsequent independent t-tests revealed that HiH volunteers allocated to the TRP+ group smoked more than those in the HiH/CTR and LoH/TRP+ groups (P's < 0.05). All the analyses of the experimental outcome measures were thus repeated with the addition of this variable as a covariate but, as this did not appear to alter any of the main effects and interactions, only the results from the original ANOVAs will be reported here.
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Several significant differences in traits and stress proneness were observed between the hostility groups. Characteristics of LoH and HiH participants are presented in Table 4.
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Salivary cortisol levels
Effects of dietary manipulation (t1 vs. t2). One subject (LoH/TRP+) failed to provide sufficient amount of saliva at baseline for the cortisol assay to be performed. Cortisol baseline levels did not differ significantly between the four experimental groups (P's > 0.20). ANOVA of cortisol percent change from baseline did not reveal any main effects or interactions (F's < 0.101, P's > 0.750). One-sample t-test of the experimental sample revealed that all participants showed a significant decline in salivary cortisol between the two time points (difference from 0: t[65] = –22.401, <0.001). Cortisol levels (nmol/l) at t1 and at t2 did not differ significantly between the four experimental groups [mean ± SEM; t1: LoH/TRP+, 19.51 ± 1.68; LoH/CTR, 18.76 ± 1.63; HiH/TRP+, 20.07 ± 1.68; HiH/CTR, 17.10 ± 1.63; and t2: LoH/TRP+, 8.33 ± 0.79; LoH/CTR, 8.24 ± 0.79; HiH/TRP+, 9.34 ± 0.81; HiH/CTR, 7.68 ± 0.79; P's > 0.20).
Effects of dietary manipulation and stress (t2 vs. t3). Inspection of box-plots representing change in salivary cortisol levels revealed seven outliers who were thus excluded from the subsequent analyses of the cortisol data (two LoH/TRP+, four LoH/CTR, one HiH/CTR; outliers were defined by SPSS software as the values more than 1.5 of the interquartile range (IQR) computed from Tukey's hinges in the box-plots). ANOVA of the change in cortisol levels revealed only a significant main effect of hostility group (F[1,56] = 7.050, P < 0.01; Figure 1). Post hoc one-sample t-tests within each of the hostility groups revealed that HiH participants displayed a significant increase in cortisol levels following stressful manipulation (difference from 0: t[31] = 3.438, P < 0.005), while the LoHs did not (P > 0.30). Diet did not significantly modulate the stress-related changes in cortisol release.
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Heart rate
Effects of dietary manipulation and stress. Due to problems with the heart rate monitoring equipment, heart rate was recorded continuously only in 48 participants (17 LoH/TRP+, 11 HiH/TRP+, 9 LoH/CTR, and 11 HiH/CTR).
ANOVA of average heart rates at four phases of the stress manipulation revealed a significant effect of time (Huynh-Feldt F[2.226, 97.952] = 35.715, P < 0.001) indicating a significant increase in heart rate during speech delivery (simple contrast comparison to baseline: F[1,44] = 47.483, P < 0.001) and the mental arithmetic task (simple contrast vs. baseline: F[1,44] = 8.796, P < 0.005). An interaction between time and hostility (Huynh-Feldt F[2.226, 97.952] = 4.937, P < 0.01) was apparent at speech preparation and speech delivery stages (simple contrast vs. baseline: F[1,44] = 5.087, P < 0.05 and F[1,44] = 7.006, P < 0.05, respectively; see Figure 2), with LoHs showing greater increase than HiHs at both time points. Dietary manipulation, however, did not modulate participants’ heart rate significantly.
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P < 0.05 — simple contrast vs. baseline (time x hostility group interaction).Mood
Means and standard errors for each hostility group at all three time points are presented in Table 5.
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Effect of dietary manipulation (t1 vs. t2). Several main effects of hostility group were observed (F's [1,63]> 5.301, P's < 0.05). Compared to LoH individuals, HiHs tended to report less of happiness and positive mood, and more of anxiety, depression, anger, and tension than LoHs across the two time points. A main effect of time point was also revealed but only with respect to POMS Depression (F[1,63] = 8.843, P < 0.005). All participants tended to report less depression at time point 2 (prestress), compared to time point 1 (baseline). Dietary manipulation, however, failed to exert significant effects on mood (no main effects of or interactions with diet).
Effect of dietary manipulation and stress (t2 vs. t3). Several main effects of time and hostility were observed. Stress increased anxiety, depression, anger, confusion, and tension while it reduced friendliness, elation, happiness, and positive mood in the majority of participants (F's > 6.891, P's < 0.05). Compared to LoHs, HiH individuals reported more of anxiety, depression, anger, and confusion, and less of positive mood across the two time points (F's > 8.217, P's < 0.010). The interaction of time point and hostility group was approaching significance with respect to POMS Anger (F[1,63] = 3.769, P < 0.06), revealing a tendency for HiH individuals to report greater increase in anger following stress induction than their LoH counterparts. However, no effects of or interactions with diet group were observed.
Craving for alcohol
Effects of dietary manipulation (t1 vs. t2). Analysis of the total Desire for Alcohol Questionnaire (DAQ) score revealed a main effect of time (F[1,63] = 32.442, P < 0.001), reflecting an increase in craving during the testing session prior to stress induction. A main effect of hostility group was also observed (F[1,63] = 9.607, P < 0.005), indicating greater craving in HiH individuals. No main effect of or interactions with diet was observed in this analysis.
Effects of dietary manipulation and stress (t2 vs. t3). Analysis of total DAQ score revealed a significant three-way interaction of time point, hostility group, and diet (F[1,63] = 4.374, P < 0.05), in addition to main effects of time (majority of volunteers reported higher craving following stress: F[1,63] = 44.152, P < 0.001) and hostility group (higher craving scores in HiH group: F[1,63] = 10.102, P < 0.005) (Figure 3.). Subsequent separate ANOVAs in each hostility group revealed that the interaction between time point and diet was significant only in HiHs (F[1,31] = 4.225, P < 0.05), while LoHs in both diet groups tended to show increased craving following stress (main effect of time: F[1,32] = 29.311, P < 0.001). Post hoc t-tests in HiH group revealed that individuals who received TRP+ diet showed a significant increase in craving following stress induction (t[15] = –4.401, P < 0.001), while individuals who received CTR diet did not show such increase (P > 0.10).
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To exclude the possibility that CTR diet actually blocked the increase in craving in HiHs and confirm that the lack of increase in craving in this group was due to already very high level of craving in HiHs at t2, an additional univariate ANOVA of percent change in craving from t2 was performed. This showed that the diet x hostility group interaction was still significant (F[1,63] = 4.041, P < 0.05) even though all four experimental groups showed a significant increase in craving following stress (t-tests from 0: t’s>2.130, P's < 0.05).
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Discussion |
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The study demonstrated that HiH individuals, as predicted, have greater disposition to negative mood (report more of anxiety, depression, anger, confusion, fatigue, negative mood, and tension, and less of positive mood and happiness) than LoH individuals. These findings are in concordance with the results reported by Felsten and Hill (1999)
, who found that high-hostile participants, compared to low hostiles, had increased anxiety, depression, and anger, as measured by POMS. HiH individuals in the present study were also characterized by greater trait anxiety and more depressive symptoms and seem to have been exposed to more stress in the month prior to participating in the study, compared to the LoH participants. Furthermore, compared to LoHs, HiHs were characterized by increased Harm Avoidance trait, suggestive of anxiety and ineffective coping strategies, and decreased Self-Directedness trait, characteristic of weak, fragile, blaming individuals who are unable to set or pursue meaningful goals, their behavior being dominated by reactions to stimulation and pressure from external circumstances (Cloninger et al., 1994; Krebs et al., 1998). Although they were not ordinarily consuming more alcohol than LoH participants, HiHs consistently reported higher craving for alcohol throughout the experimental session.
Stress induction procedure successfully altered mood (increasing anxiety, depression, anger, tension, and confusion, and decreasing friendliness, elation, positive mood, and happiness), increased cortisol secretion and heart rate, and enhanced craving for alcohol. Contrary to previous reports (Suarez et al., 1998), HiHs failed to show greater cardiovascular reactivity to stress than the LoH participants. In fact, LoH individuals in this study had significantly higher heart rate during the stress-induction procedure. On the other hand, HiH individuals did show a more robust cortisol response to stress, suggesting greater activation of the HPA axis in these individuals. This result replicates and extends the findings of a study by Suarez and colleagues (1998), who reported enhanced cortisol response to stress in high-hostile men. Interestingly, LoHs failed to show a significant cortisol response to stress, which is at odds with the greater heart rate increase observed in this group. In addition to this, a nonsignificant trend was observed for HiHs to show greater increase in anger following stress than their LoH counterparts, which replicates the findings from a previous study (Felsten and Hill, 1999).
As expected, dietary tryptophan enhancement did not appear to have any direct effect on mood, craving for alcohol, or salivary cortisol levels in the absence of stress. All participants showed a significant reduction in cortisol levels between the morning baseline and the early afternoon post-diet measurement, which probably represents the normal diurnal decline in cortisol levels. Furthermore, diet did not seem to affect either mood or physiological (salivary cortisol and heart rate) reactivity to stress. This is in contrast with findings reported by Markus and colleagues (2000a, 2000b, 1998), who consistently observed reduced physiological reactivity to stress in high stress-prone participants receiving tryptophan-enhancing diets. Moreover, contrary to predictions, TRP+ diet appeared to promote increase in subjective craving for alcohol following stress induction in HiH individuals, while stress-induced increase in craving seemed to be not affected by diet in LoHs.
According to Markus and colleagues (2002, 2000a, 1999, 2000b, 1998), individuals who are stress-prone (HiHs in the present experiment) and who are thus thought to be likely to suffer from serotonergic deficit, are expected to benefit from tryptophan enhancement in stressful situations. It is difficult to explain this discrepancy between the predicted and the observed effects of tryptophan enhancement. However, although the role of serotonin in modulating stress responsiveness (subjective and physiological) is to promote resilience to mood-lowering effects of adverse situations (Deakin and Graeff, 1991), this may be different from the yet unclear role of serotonin in modulating stress-induced alcohol-related behavior. Indeed, increased motivation to drink following tryptophan enhancement is in line with the role of serotonin in potentiating the activation of the mesolimbic DA system, which is thought to mediate incentive properties of alcohol and other appetitive stimuli (Di Chiara and Imperato, 1988; Ikemoto and Panksepp, 1999; McBride et al., 1999). Such explanation can also account for the fact that TRP+ diet enhanced craving for alcohol only after stress induction, since activity of dorsal raphe serotonergic neurones is increased during arousing situations such as stress (Jacobs and Fornal, 1999), and stimulation or inhibition of dorsal raphe neurones was found to increase or inhibit, respectively, DA release into nucleus accumbens (McBride et al., 1993). Thus the present findings may be explained in terms of a specific effect of tryptophan enhancement on the incentive value of alcohol under stress.
The complexity of serotonergic modulation of incentive value of alcohol was further highlighted by Berggren et al. (2001). Their study had demonstrated that pharmacological enhancement of 5-HT function effectively reduced alcohol consumption in heavy drinkers who showed increased release of prolactin in response to the fenfluramine challenge (index of unimpaired serotonergic function), while in those with more evident 5-HT impairment (i.e., low prolactin responders to fenfluramine) the same treatment had no effect or even promoted alcohol consumption. This finding may account for the unexpected enhancement of craving in stressed HiH but not LoH individuals in our study, following tryptophan enhancement. Indeed trait hostility was found to be inversely associated with prolactin response to serotonergic agonist m-CPP (Handelsman et al. 1996). Gerra et al. (1995a, 1995b) also found blunted prolactin response to fenfluramine in hostile heroin addicts, although this predicted better effectiveness of combined fluoxetine and naltrexone treatment for heroin addiction (Gerra et al. 1995b).
The present findings may also shed light on inconsistent reports in the literature regarding the effectiveness of serotonergic pharmacotherapy in treatment of alcohol dependence. While some studies have found fluoxetine to be effective in reducing alcohol consumption in depressed alcohol-dependent patients (Cornelius et al., 1997; Naranjo et al., 1994), others have concluded that selective serotonin reuptake inhibitors are ineffective in decreasing rates of relapse (Kabel and Petty, 1996; Kranzler et al., 1995) and may even worsen treatment outcome in a subtype of high risk/severity alcoholics who are likely to suffer from reduced serotonergic function (Chick et al., 2004; Kranzler et al., 1996).
While the differential effects of tryptophan enhancement on the two hostile groups in this study may be taken as an index of difference in their serotonergic system regulation (Dougherty et al., 1999), the nature of this difference is not clear. One explanation for the link between hostility and serotonergic function may derive by studying 5-HTTLPR gene polymorphisms. Individuals who exhibit greater reactivity to stress and susceptibility to depression are more likely to have short variant of the 5-HTTLPR (see Firk and Markus, 2007, for a review). Such possibility may also provide an explanation for the differential effect of tryptophan enhancement on craving for alcohol in low- and high-hostile individuals, which was observed in the present study. A recent study by Roiser et al. (2006) reported increased incentive motivation following tryptophan depletion in individuals with the long 5-HTTLPR allele while the treatment had the opposite effect (i.e., reduced motivation) in individuals with the short allelic variation of this gene. By this account, HiH individuals in the present study may have the short genotype since they exhibited increased motivation to drink following tryptophan enhancement. A recent report of increased negativity and suspiciousness scores (subscales of the Buss–Durkee Hostility Inventory) in heroin addicts who were also short 5-HTTLPR gene carriers (Gerra et al. 2004), supports this speculation. Further studies exploring neuropharmacological correlates of hostility are essential to better define the nature of vulnerability of high-hostile individuals to alcohol-related behaviors as well as to explore the possibility of using selective pharmacological agents to treat alcoholism in this population.
Several factors limit interpretation of the present findings. First, the fact that approximately two-thirds of the participants were female may have affected the outcome of dietary manipulation, due to menstrual cycle–related variability in responsiveness to tryptophan manipulation (Halbreich, 1990). Furthermore, the link between serotonin function and personality variables, such as impulsivity, hostility, and aggression appears to be stronger in men than in women (Manuck et al., 1998; Møller et al., 1996). Finally, tension-reduction drinking motives were found to modulate heavy drinking only in men (Cooper et al., 1992; Rutledge and Sher, 2001) while female heavy social drinkers seem to show a reduction in alcohol cue-reactivity following stress (Nesic and Duka, 2006), suggesting perhaps that the greater proportion of female participants in this experimental sample may have imposed a ceiling on the effects of diet and stress on craving for alcohol. It is therefore possible that different pattern of results would have been obtained had there been more men in the experimental sample. Second, although one of the exclusion criteria for this study was that subjects did not suffer from any psychiatric disorder (assessed by medical interview), the BDI scores of some HiH participants were well within the range consistent with clinical depression (Beck, 1987). Therefore a possibility remains that the observed effects of hostility were, in fact, effects of depression—further studies are needed to clarify this. Third, in order to conduct a more conclusive exploration of the involvement of 5-HT in trait hostility and stress-induced alcohol-related behaviors, studies employing more robust methods of tryptophan enhancement as well as depletion using amino acid tablets are needed. Finally, conclusions from the present study, which was conducted on a student sample of social drinkers, may not be extrapolated to individuals from wider community OR alcoholics; further studies are required to investigate trait hostility and susceptibility to the effects of dietary tryptophan manipulation and stress on alcohol-related behaviors in such populations.
To summarize, the findings of the present experiment suggest that high hostility confers greater susceptibility to negative mood and alcohol-related behaviors. Furthermore, tryptophan-enriched diet appeared to enhance motivation to consume alcohol after stress induction in HiH individuals, suggesting that hostility is a factor that may influence responsiveness to serotonergic therapy for alcohol abuse.
The results of the present study clearly indicate that the use of -lactalbumin supplements as a means of improving stress resilience and reducing susceptibility to alcoholism is not only unfounded but may also have the negative consequence of increasing incentive value of alcohol during stress in certain individuals, such as those characterized with high hostility trait. Furthermore, considering the sensitivity of serotonergic system to dietary composition (Yokogoshi and Wurtman, 1986), the present findings highlight the need to take dietary factors into account when evaluating vulnerability to alcoholism in heavy social drinkers.
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ACKNOWLEDGEMENTS |
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This work was supported by the Overseas Research Studentship for postgraduate studies. "Vivinal Alpha" (
-lactalbumin-enriched whey protein powder) was provided by Broculo Domo Ingredients, The Netherlands. Butter powder and sodium caseinate were provided by Garrett Ingredients Ltd, UK, and maltrodextrine was provided by Cerestar, UK. Our thanks to Dr Abi Rose and Dr Sam Knowles who helped with the food preparation, and to Dr Abdullah Badawy from Biomedical Research Laboratories, Whitchurch Hospital, Cardiff, for advice and analysis of blood samples in the pilot test of the dietary tryptophan manipulation. |
FOOTNOTES |
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1 Present address: Department of Pharmacology and Therapeutics, University of Brighton, Brighton, UK.
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References |
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TOPABSTRACTIntroductionMethodsResultsDiscussionReferences |
|---|
Badawy A. A., Evans M. Animal liver tryptophan pyrrolases: Absence of apoenzyme and of hormonal induction mechanism from species sensitive to tryptophan toxicity. Biochemistry Journal (1976) 158:79–88.[Web of Science][Medline]
Ballenger J. C., Goodwin F. K., Major L. F., Brown G. L. Alcohol and central serotonin metabolism in man. Archives of General Psychiatry (1979) 36:224–227.
Beck A. T. Beck Depression Inventory Manual (1987) New York: Harcourt Brace Jovanovich, Inc.
Berggren U., Eriksson M., Fahlke C., Balldin J. Relationship between central serotonergic neurotransmission and reduction in alcohol intake by citalopram. Drug and Alcohol Dependence (2001) 63:263–267.[CrossRef][Web of Science][Medline]
Binz U., Wendt G. KUSTA: Brief rating scale for mood and activation. In: Rating Scales for Psychiatry—AMDP, CIPS, eds. (1990) Weinheim, West Germany: Beltz Test.
Bjork J. M., Dougherty D. M., Moeller F. G., Cherek D. R., Swann A. C. The effects of tryptophan depletion and loading on laboratory aggression in men: Time course and a food-restricted control. Psychopharmacology (Berl) (1999) 142:24–30.[CrossRef][Medline]
Bjork J. M., Dougherty D. M., Moeller F. G., Swann A. C. Differential behavioral effects of plasma tryptophan depletion and loading in aggressive and nonaggressive men. Neuropsychopharmacology (2000) 22:357–369.[CrossRef][Web of Science][Medline]
Brady K. T., Sonne S. C. The role of stress in alcohol use, alcoholism treatment, and relapse. Alcohol Research and Health (1999) 23:263–271.[Web of Science][Medline]
Brown S. A., Vik P. W., McQuaid J. R., Patterson T. L., Irwin M. R., Grant I. Severity of psychosocial stress and outcome of alcoholism treatment. Journal of Abnormal Psychology (1990) 99:344–348.[CrossRef][Web of Science][Medline]
Buss A. H., Perry M. The Aggression Questionnaire. Journal of Personality and Social Psychology (1992) 63:452–459.[CrossRef][Web of Science][Medline]
Chick J., Aschauer H., Hornik K. Efficacy of fluvoxamine in preventing relapse in alcohol dependence: A one-year, double-blind, placebo-controlled multicentre study with analysis by typology. Drug and Alcohol Dependence (2004) 74:61–70.[CrossRef][Web of Science][Medline]
Cleare A. J., Bond A. J. Effects of alterations in plasma tryptophan levels on aggressive feelings. Archives of General Psychiatry (1994) 51:1004–1005.
Cleare A. J., Bond A. J. The effect of tryptophan depletion and enhancement on subjective and behavioural aggression in normal male subjects. Psychopharmacology (1995) 118:72–81.[CrossRef][Medline]
Cloninger C. R., Przybeck T. R., Svrakic D. M., Wetzel R. D. The Temperament and Character Inventory (TCI): A guide to its development and use (1994) St. Louis, MO: Center for Psychobiology of Personality.
Coffey S. F., Saladin M. E., Drobes D. J., Brady K. T., Dansky B. S., Kilpatrick D. G. Trauma and substance cue reactivity in individuals with comorbid posttraumatic stress disorder and cocaine or alcohol dependence. Drug and Alcohol Dependence (2002) 65:115–127.[CrossRef][Web of Science][Medline]
Cohen S., Kamarck T., Mermelstein R. A global measure of perceived stress. Journal of Health and Social Behavior (1983) 24:386–396.
Cooney N. L., Litt M. D., Morse P. A., Bauer L. O., Gaupp L. Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men. Journal of Abnormal Psychology (1997) 106:243–250.[CrossRef][Web of Science][Medline]
Cooper M. L., Russell M., Skinner J. B., Frone M. R., Mudar P. Stress and alcohol use: Moderating effects of gender, coping, and alcohol expectancies. Journal of Abnormal Psychology (1992) 101:139–152.[CrossRef][Web of Science][Medline]
Cornelius J. R., Salloum I. M., Ehler J. G., et al. Double-blind fluoxetine in depressed alcoholic smokers. Psychopharmacology Bulletin (1997) 33:165–170.[Web of Science][Medline]
de Wit H., Soderpalm A. H., Nikolayev L., Young E. Effects of acute social stress on alcohol consumption in healthy subjects. Alcoholism: Clinical and Experimental Research (2003) 27:1270–1277.[CrossRef][Web of Science][Medline]
Deakin J. F., Graeff F. G. 5-HT and mechanisms of defence. Journal of Psychopharmacology (1991) 5:305–315.
Delgado P. L., Charney D. S., Price L. H., Aghajanian G. K., Landis H., Heninger G. R. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Archives of General Psychiatry (1990) 47:411–418.
Denness R., Patten S. Principles of Dairy Chemistry (1959) New York: John Wiley.
Department of Health. The Health of the Nation – A Strategy for Health in England (1992) London: HMSO.
Di Chiara G., Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. In: Proceedings of the National Academy of Sciences of the USA (1988) 85:5274–5278.
Dougherty D. M., Bjork J. M., Marsh D. M., Moeller F. G. Influence of trait hostility on tryptophan depletion-induced laboratory aggression. Psychiatry Research (1999) 88:227–232.[CrossRef][Web of Science][Medline]
Fahlke C., Engel J. A., Eriksson C. J., Hard E., Soderpalm B. Involvement of corticosterone in the modulation of ethanol consumption in the rat. Alcohol (1994a) 11:195–202.[CrossRef][Web of Science][Medline]
Fahlke C., Hard E., Eriksson C. J., Engel J. A., Hansen S. Consequence of long-term exposure to corticosterone or dexamethasone on ethanol consumption in the adrenalectomized rat, and the effect of type I and type II corticosteroid receptor antagonists. Psychopharmacology (Berl) (1995) 117:216–224.[CrossRef][Medline]
Fahlke C., Hard E., Thomasson R., Engel J. A., Hansen S. Metyrapone-induced suppression of corticosterone synthesis reduces ethanol consumption in high-preferring rats. Pharmacology Biochemistry Behavior (1994b) 48:977–981.[CrossRef]
Felsten G., Hill V. Aggression Questionnaire hostility scale predicts anger in response to mistreatment. Behaviour Research and Therapy (1999) 37:87–97.[CrossRef][Web of Science][Medline]
Fichera L. V., Andreassi J. L. Cardiovascular reactivity during public speaking as a function of personality variables. International Journal of Psychophysiology (2000) 37:267–273.[CrossRef][Web of Science][Medline]
Finn P. R., Young S. N., Pihl R. O., Ervin F. R. The effects of acute plasma tryptophan manipulation on hostile mood: The influence of trait hostility. Aggressive Behavior (1998) 24:173–185.[CrossRef][Web of Science]
Firk C., Markus C. R. Review: Serotonin by stress interaction: A susceptibility factor for the development of depression? Journal of Psychopharmacology (2007) 21:538–544.
Gerra G., Fertonani G., Tagliavini P., et al. Serotonin function in detoxified heroin abusers: Prolactin and cortisol responses to fenfluramine challenge. Psychiatry Research (1995a) 58:153–160.[CrossRef][Web of Science][Medline]
Gerra G., Fertonani G., Zaimovic A., et al. Hostility in heroin abusers subtypes: Fluoxetine and naltrexone treatment. Progress in Neuropsychopharmacology and Biological Psychiatry (1995b) 19:1225–1237.[CrossRef][Medline]
Gerra G., Garofano L., Santoro G., et al. Association between low-activity serotonin transporter genotype and heroin dependence: Behavioral and personality correlates. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetic (2004) 126:37–42.
Gerra G., Zaimovic A., Sartori R., et al. Experimentally induced aggressiveness in adult children of alcoholics (ACOAs): Preliminary behavioral and neuroendocrine findings. Journal of Studies on Alcohol (1999) 60:776–783.[Web of Science][Medline]
Halbreich U. Gonadal hormones and antihormones, serotonin and mood. Psychopharmacology Bulletin (1990) 26:291–295.[Web of Science][Medline]
Handelsman L., Holloway K., Kahn R. S., et al. Hostility is associated with a low prolactin response to meta-chlorophenylpiperazine in abstinent alcoholics. Alcoholism: Clinical and Experimental Research (1996) 20:824–829.[CrossRef][Web of Science][Medline]
Higgins R. L., Marlatt G. A. Fear of interpersonal evaluation as a determinant of alcohol consumption in male social drinkers. Journal of Abnormal Psychology (1975) 84:644–651.[CrossRef][Web of Science][Medline]
Higley J. D., Bennett A. J. Central nervous system serotonin and personality as variables contributing to excessive alcohol consumption in non-human primates. Alcohol and Alcoholism (1999) 34:402–418.
Hu X., Oroszi G., Chun J., Smith T. L., Goldman D., Schuckit M. A. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcoholism: Clinical and Experimental Research (2005) 29:8–16.[CrossRef][Web of Science][Medline]
Ikemoto S., Panksepp J. The role of nucleus accumbens dopamine in motivated behavior: A unifying interpretation with special reference to reward-seeking. Brain Research Reviews (1999) 31:6–41.[CrossRef][Medline]
Jacobs B. L., Fornal C. A. Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology (1999) 21:9S–15S.[Medline]
Kabel D. I., Petty F. A placebo-controlled, double-blind study of fluoxetine in severe alcohol dependence: Adjunctive pharmacotherapy during and after inpatient treatment. Alcoholism: Clinical and Experimental Research (1996) 20:780–784.[CrossRef][Web of Science][Medline]
Kirby L. G., Rice K. C., Valentino R. J. Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus. Neuropsychopharmacology (2000) 22:148–162.[CrossRef][Web of Science][Medline]
Kirschbaum C., Pirke K. M., Hellhammer D. H. The ‘Trier Social Stress Test’–a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology (1993) 28:76–81.[Web of Science][Medline]
Kirschbaum C., Prussner J. C., Stone A. A., et al. Persistent high cortisol responses to repeated psychological stress in a subpopulation of healthy men. Psychosomatic Medicine (1995) 57:468–474.
Kranzler H. R., Burleson J. A., Brown J., Babor T. F. Fluoxetine treatment seems to reduce the beneficial effects of cognitive-behavioral therapy in type B alcoholics. Alcoholism: Clinical and Experimental Research (1996) 20:1534–1541.[CrossRef][Web of Science][Medline]
Kranzler H. R., Burleson J. A., Korner P., et al. Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. American Journal of Psychiatry (1995) 152:391–397.
Krebs H., Weyers P., Janke W. Validation of the German version of Cloninger's TPQ: Replication and correlations with stress coping, mood measures and drug use. Personality and Individual Differences (1998) 24:805–814.[CrossRef][Web of Science]
Lê A. D., Harding S., Juzytsch W., Fletcher P. J., Shaham Y. The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. Journal of Neuroscience (2002) 22:7844–7849.
Lê A. D., Poulos C. X., Harding S., Watchus J., Juzytsch W., Shaham Y. Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress. Neuropsychopharmacology (1999) 21:435–444.[CrossRef][Web of Science][Medline]
Lê A. D., Shaham Y. Neurobiology of relapse to alcohol in rats. Pharmacology & Therapeutics (2002) 94:137–156.[CrossRef][Web of Science][Medline]
LeMarquand D., Pihl R. O., Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: Clinical evidence. Biological Psychiatry (1994) 36:326–337.[CrossRef][Web of Science][Medline]
Liu X., Weiss F. Additive effect of stress and drug cues on reinstatement of ethanol seeking: Exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. Journal of Neuroscience (2002) 22:7856–7861.
Love A., James D., Willner P. A comparison of two alcohol craving questionnaires. Addiction (1998) 93:1091–102.[CrossRef][Web of Science][Medline]
Manuck S. B., Flory J. D., McCaffery J. M., Matthews K. A., Mann J. J., Muldoon M. F. Aggression, impulsivity, and central nervous system serotonergic responsivity in a nonpatient sample. Neuropsychopharmacology (1998) 19:287–299.[CrossRef][Web of Science][Medline]
Markus C. R., Olivier B., de Haan E. H. F. Whey protein rich in a-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects. American Journal of Clinical Nutrition (2002) 75:1051–1056.
Markus C. R., Olivier B., Panhuysen G., et al. The bovine protein a-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress. American Journal of Clinical Nutrition (2000a) 71:1536–1544.
Markus C. R., Panhuysen G., Jonkman L. M., Bachman M. Carbohydrate intake improves cognitive performance of stress-prone individuals under controllable laboratory stress. British Journal of Nutrition (1999) 82:457–467.[Web of Science][Medline]
Markus C. R., Panhuysen G., Tuiten A., Koppeschaar H. F. Effects of food on cortisol and mood in vulnerable subjects under controllable and uncontrollable stress. Physiology and Behavior (2000b) 70:333–342.[CrossRef][Medline]
Markus C. R., Panhuysen G., Tuiten A., Koppeschaar H. F., Fekkes D., Peters M. L. Does carbohydrate-rich, protein-poor food prevent a deterioration of mood and cognitive performance of stress-prone subjects when subjected to a stressful task? Appetite (1998) 31:49–65.[CrossRef][Web of Science][Medline]
Marlatt G. A. A cognitive-behavioral model of the relapse process. In: Behavioral Analysis and Treatment of Substance Abuse—Krasnegor N. A., ed. (1979) Rockville, MD: NIDA Research Monographs. 191–201.
McBride W. J., Murphy J. M., Ikemoto S. Localization of brain reinforcement mechanisms: Intracranial self-administration and intracranial place-conditioning studies. Behavioural Brain Research (1999) 101:129–152.[CrossRef][Web of Science][Medline]
McBride W. J., Murphy J. M., Yoshimoto K., Lumeng L., Li T. K. Serotonin mechanisms in alcohol drinking behavior. Drug Development Research (1993) 30:170–177.[CrossRef][Web of Science]
McNair D., Lorr M., Droppleman L. Profile of Mood States, Manual (1971) Educational and Industrial Testing Service, San Diego, CA.
Mehrabian A., Russell J. A. A questionnaire measure of habitual alcohol use. Psychological Reports (1978) 43:803–806.[Web of Science][Medline]
Miller P. M., Hersen M., Eisler R. M., Hilsman G. Effects of social stress on operant drinking of alcoholics and social drinkers. Behaviour Research and Therapy (1974) 12:67–72.[CrossRef][Web of Science][Medline]
Møller S. E., Mortensen E. L., Breum L., et al. Aggression and personality: Association with amino acids and monoamine metabolites. Psychological Medicine (1996) 26:323–331.[Web of Science][Medline]
Naranjo C. A., Chu A. Y., Tremblay L. K. Neurodevelopmental liabilities in alcohol dependence: Central serotonin and dopamine dysfunction. Neurotoxicology Research (2002) 4:343–361.
Naranjo C. A., Poulos C. X., Bremner K. E., Lanctot K. L. Fluoxetine attenuates alcohol intake and desire to drink. International Clinical Psychopharmacology (1994) 9:163–172.[Web of Science][Medline]
Nesic J., Duka T. Gender specific effects of a mild stressor on alcohol cue reactivity in heavy social drinkers. Pharmacology Biochemistry Behavior (2006) 83:239–248.[CrossRef]
Nesic J., Morgan C. J., Badawy A. A.-B., Duka T. Effects of tryptophan-enriched diet and stress on serum tryptophan levels and mood: The role of trait aggression. Journal of Psychopharmacology (2003) 17(Suppl):A16.
Pelham W. E., Lang A. R., Atkeson B., et al. Effects of deviant child behavior on parental distress and alcohol consumption in laboratory interactions. Journal of Abnormal Child Psychology (1997) 25:413–424.[CrossRef][Web of Science][Medline]
Piazza P. V., Le Moal M. Glucocorticoids as a biological substrate of reward: Physiological and pathophysiological implications. Brain Research Reviews (1997) 25:359–372.[CrossRef][Medline]
Piazza P. V., Le Moal M. The role of stress in drug self-administration. Trends in Pharmacological Sciences (1998) 19:67–74.[CrossRef][Medline]
Pohorecky L. A. Stress and alcohol interaction: An update of human research. Alcoholism: Clinical and Experimental Research (1991) 15:438–459.[CrossRef][Web of Science][Medline]
Roiser J. P., Blackwell A. D., Cools R., et al. Serotonin transporter polymorphism mediates vulnerability to loss of incentive motivation following acute tryptophan depletion. Neuropsychopharmacology (2006) 31:2264–2272.[Web of Science][Medline]
Rutledge P. C., Sher K. J. Heavy drinking from the freshman year into early young adulthood: The role of stress, tension-reduction drinking motives, gender and personality. Journal of Studies on Alcohol (2001) 62:457–466.[Web of Science][Medline]
Sinha R., O’Malley S. S. Craving for alcohol: Findings from the clinic and the laboratory. Alcohol and Alcoholism (1999) 34:223–230.
Smith T. W., Gallo L. C. Hostility and cardiovascular reactivity during marital interaction. Psychosomatic Medicine (1999) 61:436–445.
Spielberger C. D., Gorsuch R. I., Lushene R. E. STAI: State Trait Anxiety Inventory (Form X). In: Rating Scales for Psychiatry—AMDP, CIPS, eds. (1990) Weinheim, West Germany: Beltz Test.
Stewart J. Pathways to relapse: The neurobiology of drug- and stress-induced relapse to drug-taking. Journal of Psychiatry and Neuroscience (2000) 25:125–136.[Web of Science][Medline]
Stewart J. Stress and relapse to drug seeking: Studies in laboratory animals shed light on mechanisms and sources of long-term vulnerability. American Journal of Addiction (2003) 12:1–17.[Web of Science][Medline]
Stewart J., de Wit H., Eikelboom R. Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychological Review (1984) 91:251–268.[CrossRef][Web of Science][Medline]
Suarez E. C., Kuhn C. M., Schanberg S. M., Williams R. B. J., Zimmerman E. Neuroendocrine, cardiovascular, and emotional responses of hostile men: The role of interpersonal challenge. Psychosomatic Medicine (1998) 60:78–88.
van Praag H. M. Anxiety and increased aggression as pacemakers of depression. Acta Psychiatrica Scandinavica (Suppl) (1998) 393:81–88.
Wendt G., Binz U., Muller A. A. KUSTA (Kurz-Skala Stimmung/Aktivierung): A daily self-rating scale for depressive patients. Pharmacopsychiatry (1985) 18:118–122.[Web of Science][Medline]
Wolffgramm J., Heyne A. Social behavior, dominance, and social deprivation of rats determine drug choice. Pharmacology Biochemistry Behavior (1991) 38:389–399.[CrossRef]
Wood P. J., Kilpatrick K., Barnard G. New direct salivary cortisol and cortisone assays using the DELFIA system. (1997) Paper presented at the ACB National Meeting Focus, 1997.
Wurtman R. J., Hefti F., Melamed E. Precursor control of neurotransmitter synthesis. Pharmacological Reviews (1981) 32:315–335.[Web of Science]
Yokogoshi H., Wurtman R. J. Meal composition and plasma amino acid ratios: Effect of various proteins or carbohydrates, and of various protein concentrations. Metabolism (1986) 35:837–842.[CrossRef][Web of Science][Medline]
Young S. N., Pihl R. O., Ervin F. R. The effect of altered tryptophan levels on mood and behavior in normal human males. Clinical Neuropharmacology (1988) 11(Suppl_1):S207–215.[Web of Science][Medline]
Young S. N., Smith S. E., Pihl R. O., Ervin F. R. Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology (1985) 87:173–177.[CrossRef][Medline]
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