Progress in Neuro-Psychopharmacology and Biological Psychiatry
BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal
Introduction
The activity of the mesocorticolimbic dopaminergic reward circuit has been frequently associated with mediation of drug-specific rewarding effects and drug seeking behaviour (Pierce and Kumaresan, 2006). Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are both neurotrophic neuropeptides (Chao et al., 2006) that have been implicated in the survival and differentiation of adult dopamine neurons (Airaksinen & Saarma, 2002, Akaneya et al., 1995, Altar et al., 1994, Altar et al., 1992).
There are various study results that show a modulating role of BDNF in the development and maintenance of addictive behaviour (for review see (Corominas et al., 2007)). Regarding alcohol dependence it has been hypothesized that BDNF expression is associated with decreased alcohol consumption (Jeanblanc et al., 2006). In particular, acute ethanol intake in rats has been associated with increased BDNF expression, whereas prolonged ethanol intake (in excess of 24 h) resulted in decreased BDNF expression in the investigated brain regions (Logrip et al., 2009, McGough et al., 2004). Moreover, decreased expression of BDNF was associated with increased ethanol preference in the investigated rats (McGough et al., 2004). Regarding peripheral blood levels of BDNF in alcohol-dependent patients contradictory results have been reported. For example, Huang et al. (Huang et al., 2008) reported significantly increased BDNF serum levels on day 7 of alcohol withdrawal compared to healthy controls. Moreover, they found a positive association between baseline BDNF levels and withdrawal severity measured by the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). Lee et al. (Lee et al., 2009) reported significantly increased BDNF blood levels in male alcohol-dependent patients compared to healthy controls. In contrast, Joe et al. (Joe et al., 2007) found BDNF blood levels to be significantly reduced in alcohol-dependent patients that had abstained for more than 30 days.
GDNF has also been hypothesized to be involved in the regulation of addictive behaviours (Ron and Janak, 2005): preclinical study results suggest that GDNF may be a negative regulator of alcohol consumption (Carnicella et al., 2009, Carnicella et al., 2008). Consistent with this hypothesis Carnicella et al. (Carnicella et al., 2008) reported that central GDNF treatment (injected in the ventral tegmental area) decreased operant alcohol self-administration in rats. However, there are no clinical study results that show alterations of peripheral blood levels of GDNF in alcohol-dependent patients.
In respect to study results mentioned above the aims of this study were to investigate (1) alterations of serum levels of BDNF and GDNF in alcohol-dependent patients compared to healthy controls, (2) the course of BDNF and GDNF during alcohol withdrawal and (3) possible associations with psychometric dimensions of alcohol withdrawal.
Section snippets
Materials and methods
The present study was part of a large prospective research project (Studies in Neuroendocrinology and Neurogenetics in Alcoholism (NENA)(Heberlein et al., 2010) approved by the local Ethics Committee of the University of Erlangen-Nuremberg. The investigation was conducted in accordance with the Declaration of Helsinki of 1975 (revised 1983). Each participant gave written informed consent. Because animal studies suggest gender differences regarding the regulation of neurotrophic neuropeptides (
Statistical analysis
The hypothesis of normal distribution of BDNF and GDNF serum levels was rejected by means of the Kolmogorow–Smirnov test. Therefore BDNF and the GDNF serum levels were log-transformed in order to reach normal distribution. Correlations between the log-transformed BDNF and GDNF serum levels, blood parameters and psychometric dimensions of alcohol withdrawal were calculated by Pearson's correlation coefficient. Group to group differences between the BDNF and the GDNF serum levels of the
Results
Sociodemographic data of the patient group are shown in Table 1. BDNF and GDNF serum levels were not significantly associated with body mass index (BMI) (r = − 0.187, p = 0.096 (BDNF, day 1), r = − 0.019, p = 0.894 (GDNF, day 1)), age (r = 0.089, p = 0.427 (BDNF, day 1), r = − 0.043, p = 0.765 (GDNF, day 1)) and the daily amount of alcohol drinking (DI) of the alcohol-dependent patients (r = − 0.053, p = 0.643 (BDNF, day 1), r = − 0.155, p = 0.294 (GDNF, day 1)). BDNF and GDNF serum levels did not differ significantly in
Association between BDNF and GDNF and further blood parameters
BDNF serum levels were significantly associated with thrombocyte count (TC) (r = 0.325, p = 0.003) and gamma glutamyl transferase (GGT) (r = − 0.247, p = 0.025). BDNF was not significantly associated with leukocyte count (LC) (r = 0.033, p = 0.766), aspartate aminotransferase (AAT) (Spearman's rho = − 0.087, p = 0.436), alanine aminotransferase (ALAT) (r = − 0.144, p = 0.196) and creatinine (r = − 0.097, p = 0.387).
There was no significant association between GDNF and TC (r = − 0.002, p = 0.990), LC (r = − 0.014, p = 0.921), AAT (r =
Alterations in alcohol-dependent patients compared to healthy controls
- (1)
BDNF serum levels in alcohol-dependent patients
BDNF serum levels of the patient group did not differ significantly from BDNF serum levels obtained from the healthy control group (day 1: t = 0.407, p = 0.685, day 7: t = − 1.112, p = 0.269, day 14: t = 0.203, p = 0.840). BDNF serum levels did not change significantly during alcohol withdrawal (F = 1.336, p = 0.265).
- (2)
GDNF serum levels in alcohol-dependent patients
GDNF serum levels were significantly reduced in the patient group compared to the healthy control group
Associations with psychometric dimensions of alcohol withdrawal
BDNF serum levels on day 1 were significantly negatively correlated to severity of alcohol withdrawal measured by the CIWA-Ar on day 1 (r = − 0.311, p = 0.004). Influence of CIWA-Ar score of day 1 on BDNF serum levels of day 1 of withdrawal was verified by regression analysis. Therefore log-transformed BDNF serum levels were set as dependent variable and TC, GGT and CIWA-Ar score were set as independent variables. Stepwise exclusion of less significant factors showed that BDNF serum levels were
Group to group differences in alcohol intoxicated versus early abstinent patients
BDNF serum levels were significantly increased in group B compared to group A (day1: t = 0.222, p = 0.030) on day 1. BDNF serum levels of both subgroups were not significantly different from BDNF serum levels of the control group (Group A: day 1: t = − 1.463, p = 0.148, day 7: t = − 0.547, p = 0.586, day 14: t = − 1.261, p = 0.222, Group B: day 1: t = 0.806, p = 0.422, day 7: t = − 0.848, p = 0.399, day 14: t = 1.177, p = 0.242).
GDNF serum levels were not significantly altered in group A compared to group B (day 1: t = 0.614, p =
Discussion
In this study we found no significant alterations between BDNF serum levels of healthy controls and alcohol-dependent patients. BDNF serum levels did not change significantly during alcohol withdrawal. This result is contrary to results obtained by Huang et al. (Huang et al., 2008), who reported about a non-significant trend towards decreased BDNF serum levels in alcohol-dependent patients and an increase of BDNF serum levels during alcohol withdrawal. Moreover, contrary to the results obtained
Conclusion
In summary our results show that GDNF serum levels are significantly reduced in alcohol-dependent patients, whereas BDNF serum levels do not differ significantly between alcohol-dependent patients and the healthy control group. We found a significant association between BDNF serum levels and withdrawal severity. GDNF serum levels were significantly associated with psychometric measurement of alcohol tolerance. Future investigation should focus on a potential association between central
Acknowledgments
We gratefully acknowledge the assistance in recruiting patients by Rafael Riera and the stuff of the Clinic for Psychiatry, Psychotherapy and Psychosomatics Kutzenberg (Obermain). We thank Regine Heberlein, PhD, for language editing.
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