Environmental cues, alcohol seeking, and consumption in baboons: effects of response requirement and duration of alcohol abstinence

BACKGROUND: Environmental stimuli (cues) that have been paired with alcohol drinking may evoke classically conditioned states that in turn influence alcohol consumption and relapse to heavy drinking. Animal models using chained schedules of alcohol reinforcement may be useful for examining such complex interactions. METHODS: Alcohol drinking was established in 4 baboons. A sequence of lights and tones was presented during daily 3-hour sessions. First, cues were presented alone and no programmed contingencies were in effect. Second, cues were paired with 3 linked components consisting of different behavioral contingencies leading to and concluding with access to alcohol for self-administration in the last component (i.e., a chained schedule of alcohol reinforcement). Third, the effects of withholding alcohol access (i.e., forced abstinence) and increasing the number of lever responses required per drink were evaluated. RESULTS: Cues paired with a chained schedule of alcohol reinforcement engendered behaviors that brought baboons into contact with alcohol-related cues and occasioned operant responding that facilitated access to alcohol (alcohol seeking) during components that preceded alcohol access. Increasing the response requirement for each drink decreased the number of drinks and volume of alcohol consumed, but did not alter alcohol seeking. On the first session after 14 days of alcohol abstinence, latency to complete the operant requirement that produced alcohol access was decreased while both alcohol self-administration and volume of alcohol consumed were increased. CONCLUSIONS: Alcohol self-administration and consumption were sensitive to increases in response requirement and duration of alcohol abstinence, while seeking was only enhanced by duration of alcohol abstinence. This animal model may be useful to further examine the interactions between environmental cues and behaviors associated with seeking and consumption of alcohol and to evaluate the efficacy of potential alcohol treatment drugs on these behaviors.     

Fluoxetine Attenuates Adrenocortical but Not Subjective Responses to Cocaine Cues

Preclinical data suggest a link between stress reactivity and cocaine self‐administration by rodents. Serotonin appears to modulate the hypothalamic‐pituitary‐adrenal (HPA) axis. We studied the effects of chronic treatment with the serotonin reuptake inhibitor fluoxetine 40 mg/day on subjective and hormonal responses to cocaine cues in 22 subjects participating in a controlled clinical trial for cocaine dependence. Fluoxetine antagonized the cue‐induced increase in cortisol but increased subjects' ratings of the likelihood of cocaine use in response to cocaine cues. Cortisol response to cocaine cues was not related to subjective craving. Activation of the HPA axis by cocaine cues does not appear to be a necessary mediator of cue‐induced craving.     

Baclofen for alcohol dependence: a preliminary open-label study

BACKGROUND: Recent preclinical and clinical studies have shown that the gamma-aminobutyric acid-B agonist baclofen may be an effective treatment for reducing alcohol consumption. This preliminary open-label investigation examined the tolerability and effect of a 30-mg daily baclofen dose for reducing drinking, subclinical anxiety and depressive symptoms, and craving in alcohol-dependent subjects. METHODS: Nine men and three women participated in a 12-week trial during which they took baclofen on a 10 mg thrice-daily regimen and received four sessions of motivational enhancement therapy. Each participant received a comprehensive physical and psychiatric screening before being enrolled. At each visit, side effects were monitored with a revised version of the Systematic Assessment of Treatment Emergent Events-General Inquiry, and drinking data were collected via the timeline follow-back interview. Participants also completed the Beck Depression Inventory, the Beck Anxiety Inventory, and the Penn Alcohol Craving Scale at each visit. RESULTS: Baclofen was reasonably tolerated. Two participants discontinued because of side effects. No serious adverse events were noted. Six other individuals did not complete the trial. Overall, there were statistically significant reductions in the number of drinks per drinking day and the number of heavy-drinking days, and there was an increase in the number of abstinent days. Significant decreases in anxiety and craving were also shown. CONCLUSIONS: These findings suggest that baclofen is reasonably tolerated in an alcohol-dependent population, although the high dropout rate in the study is of concern. Baclofen may be effective for the reduction of drinking, anxiety, and craving for some alcohol-dependent individuals. A larger-scale placebo-controlled study is needed to further explore these effects and to determine the characteristics of those who respond to this medication.     

Core Heritable Personality Characteristics and Relapse in Alcoholics

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were David S. Janowsky and Jan Fawcett. The presentations were (1) The tridimensional personality questionnaire: Predictor of relapse in detoxified alcoholics, by Kurt Meszaros; (2) Novelty seeking predicts clinical trial attrition in alcoholics, by Jan Fawcett; (3) Personality and alcohol/substance use disorder patient relapse and attendance at self-help group meetings, by David S. Janowsky; and (4) A three-pathway psychobiological model for craving for alcohol, by Roel Verheul.     

Role of appetite-regulating peptides in alcohol craving: an analysis in respect to subtypes and different consumption patterns in alcoholism

BACKGROUND: A role of appetite-regulating peptides like leptin and ghrelin in the neurobiology of alcohol craving has been proposed by several studies. Aim of this analysis was to search for differences regarding an association between these peptides and alcohol craving with respect to different subtypes and beverage consumption patterns in patients with alcohol dependence. METHODS: We analyzed a sample of 188 patients at admission for alcohol detoxification regarding leptin and ghrelin (n=117) serum levels. Craving was measured using the Obsessive Compulsive Drinking Scale (OCDS). Patients were classified according to Lesch's typology of alcohol dependence and according to their preferred type of alcoholic beverage (beer, wine, spirits). RESULTS: Using general linear models to analyze a possible interaction between subtypes and leptin/ghrelin levels with respect to craving, we found a significant positive association for leptin in patients of Lesch's types 1 and 2, and in patients consuming beer or wine. Ghrelin levels showed a significant trend regarding an association with craving in patients of Lesch's type 1. In the other subgroups we found no significant results. CONCLUSIONS: Our findings show that appetite-regulating peptides may be of special importance regarding alcohol craving in subtypes of patients. This may explicate at least in part previous contradictory findings.     

Using the cue-availability paradigm to assess cue reactivity

BACKGROUND: A recent meta-analysis on cue-reactivity research revealed that cue-specific craving for alcohol is substantially less robust than craving measured for other drugs of abuse. The small effect sizes for alcohol underscore the need for more powerful methods of assessing cue reactivity in humans. The cue-availability paradigm is a modification of the conventional cue-reactivity paradigm and is intended to increase the sensitivity of measuring cue-reactivity to alcohol in humans. METHODS: Seventeen non-treatment-seeking alcoholics were tested individually on two different sessions (after priming with alcohol and after priming with placebo-alcohol). Subjects were presented with a total of 32 cue-availability trials. On each trial, subjects were presented with either a target cue (alcohol) or a neutral cue (water). Each cue was available for drinking on 50% of the trials (availability condition). Cue-reactivity measures were self-reports of craving and mood. RESULTS: The alcohol prime had a robust effect on craving. Irrespective of the availability of the cue for consumption or the type of cue, craving was consistently higher when subjects were primed with alcohol than with placebo-alcohol. Negative mood was also higher when it was assessed after the alcohol prime. Negative mood decreased in alcohol-primed subjects when the alcohol cue was available for consumption. The alcohol cue also had a significant, although more modest effect on craving. The alcohol cue consistently elicited higher levels of craving relative to the water cue. CONCLUSIONS: These data suggest that the priming effects of alcohol may be a significant factor contributing to the experience of craving and maintenance of drinking. The study also introduces the cue-availability as an additional new method for investigating manipulations of cue-reactivity in alcoholics.     

Measuring craving: an attempt to connect subjective craving with cue reactivity

BACKGROUND: Better insight into craving may contribute to the development of more efficient relapse prevention strategies. Inconsistent findings on the relation between craving and relapse may be due to difficulties in the measurement of craving. These difficulties are accounted for by 3 interrelated problems: lack of consensus regarding the definition of craving, the use of different time frames (craving now vs craving in the past), and lack of concordance between self-reported craving and psychophysiological measures of cue reactivity. The aim of this study is to develop and validate a new self-report questionnaire for the assessment of the core aspects of craving, taking into account different time frames and emphasizing the psychophysiological aspects of craving. It is hypothesized that this questionnaire will show higher concordance with measures of cue reactivity than existing self-report craving questionnaires. METHODS: Based on a semantic mapping sentence, a 24-item self-report questionnaire was developed: the Jellinek Alcohol Craving Questionnaire (JACQ). The questionnaire was tested in 2 samples of treatment-seeking alcohol-dependent patients (sample A, n = 251; sample B, n = 48). Psychometric properties were examined in sample A and cross-validated in sample B. The associations with psychophysiological and neuroendocrine measures of cue reactivity were studied in sample B. RESULTS: The JACQ consists of 1 dimension with the following 4 aspects: (1) emotional urge, (2) physical sensations, (3) temptation to drink, and (4) uncontrolled thoughts. All (sub)scales had a good internal consistency (alpha = 0.77-0.95) and were highly intercorrelated (r = 0.57-0.86). Craving-past correlated low with craving-now (r = 0.32). Craving-now (sub)scales showed a moderate association with heart rate (0.46-0.49), but not with respiration rate, skin conductance, or cortisol production in saliva following cue exposure. In contrast, craving-past (sub)scales showed a moderate association with cortisol production in saliva (0.15-0.42) following cue exposure. Remarkably, the physical symptoms scale did not show stronger association with psychophysiological and neuroendocrine measures than the other subscales. CONCLUSIONS: The JACQ reliably measures 1 dimension including 4 aspects of craving for distinct time frames. Despite the presence of a special subscale for physical sensations, only moderate relationships were found between self-reported craving and biological indicators of cue reactivity. These findings suggest individual differences between alcoholics in the detection and/or reporting of cue-related psychophysiological signs as indicators of cue reactivity. Further research should focus on the nature of these individual differences. In addition, more research is needed on the relative predictive validity of subjective phenotypic indicators of craving (such as self-reported craving) versus objective endophenotypic indicators of craving (such as physiological measures of cue reactivity) for example in the prediction of relapse.     

Dissociation of alcohol-seeking and consumption under a chained schedule of oral alcohol reinforcement in baboons

Background:  Initiation and maintenance of compulsive alcohol drinking involves a sequence of behaviors which occur in the presence of environmental cues. Animal models using chained schedules of alcohol reinforcement may be useful for examining the complex interactions between cues and alcohol-seeking and -consumption.
Methods:  Four baboons self-administered alcohol under a 3-component chained schedule of reinforcement; distinct cues were presented in the context of different behavioral contingencies associated with gaining access to 4% w/v alcohol (alcohol-seeking) and concluding with alcohol self-administration. First, the response strength of alcohol-related seeking responses was evaluated using a between-sessions progressive ratio (PR) procedure in which the response requirement to initiate the final contingency and gain access to the daily supply of alcohol was increased each session. The highest response requirement completed that resulted in alcohol access was defined as the breaking point (BP). Second, water was substituted for alcohol and PR procedures were repeated. The effects of increasing the "seeking" response requirement on subsequent alcohol or water consumption were also determined.
Results:  When alcohol was available, operant responses to gain access to and self-administer alcohol were maintained. When water was substituted for alcohol, alcohol-related cues continued to maintain alcohol-seeking responses. However, higher BPs, higher rates of self-administration and higher volumes of intake occurred when alcohol was available compared with water. Increasing the response requirement to gain access to alcohol did not reduce alcohol consumption (total alcohol intake).
Conclusions:  These results show that alcohol-related cues maintained alcohol-seeking even after a prolonged period of only water availability. Cue-maintained alcohol-seeking behavior can be dissociated from subsequent alcohol consumption.