Department of Psychiatry, University Hospital of Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany
Received 28 February 2002; in revised form 26 April 2002; accepted 26 April 2002
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ABSTRACT |
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INTRODUCTION |
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Based on these findings, two questions seem relevant: (1) does leptin itself mediate alcohol craving in addicts; (2) what might be the pathophysiological mechanism that links alcohol intake with increased leptin plasma levels in normal weighted alcohol addicts?
Regarding question (1), we tested the hypothesis whether application of exogenous leptin modulates voluntary alcohol consumption in mice. We found free-choice ethanol consumption in mice habituated to ethanol to be significantly elevated after intraperitoneal (i.p.) injection of a 1 mg/kg dose of leptin, indicating a positive alcohol-deprivation effect (Kiefer et al., 2001c). We suggested that leptin may enhance motivation for alcohol consumption in habituated mice after alcohol withdrawal.
To answer question (2), we have now conducted a study of whether TNF- might represent the link that connects alcohol intake with increased leptin plasma levels. This focus on TNF-
is based upon the rationale that TNF-
and TNF-
-inducible leptin mRNA levels have been shown to be increased after chronic intake of ethanol in rats independently of calorie consumption (Lin et al., 1998
). White adipose tissue was proposed to be an important source of cytokines in non-obese subjects and was suggested to be a target for ethanol's actions. Moreover, since leptin levels have been reported to be directly increased after injection of TNF-
(Barbier et al., 1998
), a pathway including alcohol intake, TNF-
increase, and leptin increase seemed possible. To test this hypothesis, we studied TNF-
secretion, leptin levels and craving in a sample of alcohol addicts with a well-documented history of alcoholism. Since craving in alcoholics is regularly detectable during alcohol withdrawal, we investigated the sample during an inpatient detoxification and abstention programme. Additionally, we chose to measure plasma concentrations of cortisol to identify mutual interactions with the HPA axis activity.
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SUBJECTS AND METHODS |
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Drug screening for benzodiazepines, opioids, cannabinoids, cocaine and amphetamines revealed negative results in all patients and controls. None of the patients or controls showed any symptoms of inflammatory, cardiac, endocrine, renal or hepatic disease, except of nutrient fatty liver disease in the inpatient sample.
The study protocol was in accordance with the Declaration of Helsinki (1964) and was approved by the Local Ethics Committee. All subjects gave written informed consent prior to the investigation.
Testing procedures
Blood samples (9 ml each) for determination of plasma TNF-, plasma leptin, plasma cortisol levels by radioimmunoassay (RIA), and routine laboratory parameters were drawn at 09:00, 1525 h after the last alcohol intake. Basic data were obtained with a structured interview. Craving was assessed with the German version of the ObsessiveCompulsive Drinking Scale (OCDS) (Anton et al., 1996
; Mann and Ackermann, 2000
) including three 100 mm visual analogue scales (VAS) concerning mean and maximum craving and its frequency.
Assay procedures
Blood samples were drawn into EDTA-coated tubes, cooled, and immediately centrifuged; plasma was collected in aliquots stored at 80°C until analysis.
TNF- concentrations were analysed using a commercially available RIA kit with the coated tube technique (DRG Diagnostics, Mountainside, NY, USA). The detection limit was 3.0 ng/ml plasma; intra- and interassay coefficients of variation (CVs) were <9%.
For measuring leptin, a human leptin RIA kit (Linco, St Louis, MO, USA) was used. The detection limit was 0.25 ng/ml plasma; intra- and interassay CVs for levels of 4.9 and 15.7 ng/ml were <8.5%. Plasma cortisol concentrations were analysed using a commercially available RIA kit with the coated tube technique (ICN Biomedicals, Carson, CA, USA). The detection limit was 0.3 ng/ml plasma; intra- and interassay CVs for 20 and 40 ng/ml levels were <7%. Laboratory parameters of alcohol misuse were measured using standard clinical chemistry analyses.
Data analysis
All data are expressed as means ± SD. For the statistical analysis of group effects regarding hormone levels, analysis of variance followed by post hoc Bonferroni's correction was applied. Whenever a significant F-ratio was detected, means were compared using independent-sample t-tests. Normal distribution of data was tested with the KolmogoroffSmirnov test. Correlations were analysed using Pearson's correlation coefficients. Statistical significance was accepted at P < 0.05.
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RESULTS |
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Associations with alcohol-related data and craving
TNF- was highly associated with the duration of alcohol misuse (years since first alcohol-related problems occurred; r = 0.43; P < 0.02) but without any relation to self-rated alcohol craving (Fig. 1
). However, leptin plasma levels correlated significantly with alcohol craving measured with the VAS for maximal craving (66.6 ± 35.4; r = 0.32, P < 0.05). Despite the significant correlation of maximal craving with other craving measures (mean craving: r = 0.70; P < 0.001; craving frequency: r = 0.59; P < 0.001; OCDS sum score: r = 0.48; P < 0.01), the correlation of leptin with mean craving (53.3 ± 35.3), craving frequency (48.9 ± 40.0), or the OCDS sumscore (30.4 ± 7.9) did not reach statistical significance. There was no association of TNF-
, leptin or cortisol with the number of inpatient detoxifications, mean amount of alcohol consumed daily during the last months prior to admission or tobacco consumption (data not shown). Plasma cortisol was without any relationship to duration of alcoholism or craving.
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DISCUSSION |
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In two independent studies, an initial study with 20 alcoholics (Kiefer et al., 2001b) and a replication study with 78 alcoholics (Kiefer et al., 2001a
), our group found elevated plasma leptin levels at the onset of withdrawal to be significantly correlated with self-rated craving. Moreover, in alcohol-habituated mice, the application of leptin (1 g/kg i.p.) resulted in an increased free-choice alcohol intake after a 3-day period of alcohol withdrawal (Kiefer et al., 2001c
). This positive so-called alcohol-deprivation effect reflects an accepted model for testing addictive behaviour and craving in animals (Spanagel and Holter, 1999
). Interactions of leptin with reinforcing brain functions that could explain the effects of leptin on craving have been reported by Fulton et al. (2000). They showed that the effectiveness of a rewarding electrical stimulation was attenuated by intracerebroventricular infusion of leptin. From their point of view, this reflects the comparative process believed to underlie behavioural allocation (Maffei et al., 1995
) with reducing food reward, while enhancing the value of competing behaviours. We think this might explain the positive association of increased alcohol craving with elevated plasma leptin in our alcoholic sample. In accordance with earlier studies on pharmacological effects on alcohol craving (Kiefer et al., 2001a
,b
), the measure maximum craving seemed to be most sensitive for the detection of short-term variations during acute alcohol withdrawal. In contrast to the measures mean craving, frequency of craving and the OCDS sum score, maximum craving describes neither a mean score nor cumulative measures of 1 week, but one maximal measure experienced during 1 week. However, there was no direct association between TNF-
and craving, suggesting that the TNF-
-mediated leptin increase might be the behaviour modulator of this pathway. Taken together, we found evidence that TNF-
might mediate an increase of plasma leptin after chronic alcohol intake. Additionally, leptin was shown to be associated with appetite for alcohol and alcohol craving. Alcohol craving, defined as an urge to consume alcohol, has been associated with an enhanced probability of renewed alcohol intake (Anton, 1999
). Hence, a possible vicious circle including the components alcohol intake, increase of TNF-
, enhanced leptin secretion, enhanced alcohol craving, and consecutively increased alcohol intake, is suggested. Further research should establish the validity of this hypothesis and may help to understand the neurobiological mechanisms of origin and maintenance of alcoholism serving as a gateway for the development of new pharmacological strategies in the therapy of addiction.
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FOOTNOTES |
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