Elsevier

Psychoneuroendocrinology

Volume 36, Issue 10, November 2011, Pages 1562-1569
Psychoneuroendocrinology

BDNF Val66Met polymorphism is associated with higher anticipatory cortisol stress response, anxiety, and alcohol consumption in healthy adults

https://doi.org/10.1016/j.psyneuen.2011.04.010Get rights and content

Summary

Background

The brain-derived neurotrophic factor (BDNF) is a key protein in maintaining neuronal integrity. The BDNF gene is thought to play an important role in the pathophysiology of mood and anxiety disorders. The aim of this study was to investigate, for the first time in a single study, the association between BDNF Val66Met polymorphism, anxiety, alcohol consumption, and cortisol stress response.

Method

98 healthy university students (54 females and 44 males), genotyped for the Val66Met polymorphism, participated in a physical-stress procedure (cold pressure test, CPT) after having been informed that they would undergo a painful experience. Indices of anxiety and of stress were collected from repeated measurement of salivary cortisol, blood pressure, and heart rate.

Results

BDNF Met carriers, were more anxious during the CPT (p < 0.001), drank more alcohol per week, (p < 0.05), and showed significantly higher anticipatory cortisol response (p < 0.05), but not in response to the CPT, than Val/Val homozygotes. The association of BDNF Val66Met polymorphism with HPA axis reactivity to stress was not modulated by gender. These results suggest that Met carriers are particularly sensitive in anticipating stressful events, which extends previous findings on the moderating role of the BDNF Val66Met polymorphism in the face of stressful life events.

Introduction

Cortisol is traditionally viewed as the most important stress hormone in humans (Sapolsky et al., 2000). In recent years cortisol has been shown to play a much broader role in human functioning (Erickson et al., 2003). Several authors have attributed various problems in health and wellbeing to the impaired attunement of individuals to their environment, as a consequence of a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis – the major pathway for regulating stress responses – and its cortisol production (e.g. McEwen, 1998b, Corbett et al., 2009).

A neurotrophin that has been shown to regulate the HPA response to stress is the brain-derived neurotrophic factor (BDNF). BDNF is a critical regulator of the formation, plasticity, and integrity of neurons in brain circuits that regulate emotion (Angelucci et al., 2005, Duman and Monteggia, 2006). In animals, exposure to stress early in life (for example, repeated maternal separation) has been found to induce a relative decrease in the expression of BDNF and to subsequent neuronal atrophy and degeneration in the hippocampus and the cortex, which can persist into adulthood (Murakami et al., 2005, Roceri et al., 2004, Song et al., 2006). Duman and Monteggia (2006) suggested that decreased expression of BDNF contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment. Along the same line, Sertoz and colleagues (2008) suggest that low BDNF might be associated with burnout symptoms including altered mood and cognitive functions. The interaction between BDNF and HPA is even more complicated by evidence suggesting that neuroactive steroids, as dehydroepiandrosterone (DHEA), pregnenolone (PREG), modulate both HPA axis and BDNF protein levels (Naert et al., 2007). Moreover, it seems that in men plasma BDNF levels, as well as cortisol levels, are significantly higher in the morning than in the night (Begliuomini et al., 2008).

A promising functional single nucleotide polymorphism (SNP) that leads to an exchange of amino acids from valine (Val) to methionine (Met) has been found at codon 66 in the 5′ pro domain of the BDNF gene (Egan et al., 2003). The Met allele is associated with a decrease in activity-dependent secretion of BDNF compared to the Val allele (Egan et al., 2003). Given that the Met/Met homozygote variant occurs in only 2–3% of the Caucasian population, most studies have compared carriers of a Met allele (Val/Met) with individuals who are homozygous for the Val allele (Val/Val). Interestingly, Shalev et al. (2009) showed that BDNF Val66Met is associated with HPA axis reactivity to psychological stress: male Val/Val homozygotes showed a greater rise in salivary cortisol than Val/Met heterozygotes, while female participants exhibited a trend towards the opposite response. Along the same line, Schüle et al. (2006) showed, by means of the fluorescence resonance energy transfer method (FRET), that Met carriers were associated with a significantly higher HPA axis activity during the dexamethasone/CRH test than Val/Val homozygotes.

Vinberg et al. (2009) demonstrated that individuals at high risk of affective disorders and who are Met carriers may exhibit an enhanced stress response. However, the altered stress response may be expressed only in combination with other risk variants through interactions with the environment. Furthermore, Elzinga et al. (2011) showed that BDNF Val66Met moderated the effects of childhood abuse and recent stress on BDNF levels, with the Met carriers with a history of childhood abuse (CA) having lower BDNF levels compared to Met carriers without a history of CA, whereas this pattern was reversed in the Val/Val group. Moreover, Met carriers have also been found to be more anxious and depressed, both in animal studies (Chen et al., 2006) and in human studies (Jiang et al., 2005, Frodl et al., 2008, Gatt et al., 2009, Montag et al., 2009, Montag et al., 2010, Verhagen et al., 2010). In contrast to all these studies, Lang et al. (2005) found higher anxiety scores, as measured by the State Trait Anxiety Inventory (STAI), which allows anxiety to be quantified as a comparatively stable personality trait, in Val/Val homozygous individuals compared to Met carriers.

Besides being involved in regulating the HPA axis, the BDNF Val66Met polymorphism seems to be involved in alcohol addiction, craving, and withdrawal (for a review, see Davis, 2008). First, the Met/Met BDNF polymorphism has been associated with alcoholism in violent alcoholics (Matsushita et al., 2004). Second, animal and in vitro studies suggest that short-term exposure to alcohol may increase BDNF levels in an effort to maintain homeostasis, but that long-term alcohol use causes both a decrease in BDNF levels in the hippocampus and hippocampal atrophy. In humans, Korean alcoholic patients were shown to have lower plasma BDNF levels (Joe et al., 2007). All these studies suggest that both low BDNF levels and the Met allele are associated with long-term alcohol use.

Interestingly, the number of alcohol units consumed per week and heavy drinking are positively associated with plasma cortisol levels (Gianoulakis et al., 2003) and salivary cortisol levels (Badrick et al., 2010). Dai et al. (2002) found that a single drink in advance of a stressor prevented the cortisol response to that stressor.

The purpose of the present study was to bring the pieces of this puzzle together in order to understand the multifaceted relation between BDNF Val66Met polymorphism, HPA axis reactivity, anxiety, and alcohol consumption. Furthermore, we aimed at extending previous findings of Shalev et al. (2009) and investigate whether physical stress may also induce higher cortisol stress response in association with the BDNF Val66Met polymorphism. In order to do that, healthy university students, genotyped for the Val66Met polymorphism, we asked to participate in a physical-stress procedure (cold pressure test: CPT) and informed beforehand that this would be a painful experience. Indices of anxiety and of stress were collected from repeated measurement of salivary cortisol, blood pressure, and heart rate. To test whether anxiety and/or general neurotic trait may be correlated with alcohol consumption in Met carriers, participants filled out a personality trait questionnaire. We expected Met carriers to show higher cortisol levels in response to the cold pressure test, to be more anxious, and to consume more alcohol than Val/Val homozygotes.

Section snippets

Participants

98 young Caucasian healthy adults (44 male/54 female), with a mean age of 22.2 years (SD = 2.6, range 18–30), served as participants for partial fulfilment of course credit or a financial reward. The sample was drawn from 110 adults in the Leiden and Rotterdam Metropolitan area (The Netherlands), who volunteered to participate in studies of behavioral genetics. Participants were recruited via ads posted on community bulletin boards and by word of mouth. Exclusion criteria were any major medical

Salivary cortisol

Table 1 provides an overview of the mean score at different time points for cortisol levels. Given that the menstrual cycle and oral contraceptives have been reported to impact salivary cortisol in social stress paradigm (Kirschbaum et al., 1999), we first compared cortisol measures obtained from women who were using oral contraception (OC+, n = 38) and from women who did not (OC−, n = 16) with those from men. As no reliable differences were obtained, F(1,52) = 0.94, p = 0.31, η2 = 0.02, F(1,80) = 0.004, p =

Discussion

The present study, for the first time, attempted to understand the multifaceted relation between BDNF Val66Met polymorphism, and stress reactivity – as measured in terms of HPA axis reactivity – anxiety, and alcohol consumption. Met carriers reported significantly stronger feelings of anxiety, nervousness, and insecurity during the CPT, and generally higher scores in social anxiety, than Val/Val homozygotes. The same Met carriers consumed significantly more alcohol per week and showed a

Role of funding sources

The research of Lorenza S. Colzato, Bernhard Hommel, Bernet Elzinga and Willem van der Does is supported by NWO (Netherlands Organization for Scientific Research).

Conflicts of interest

All authors declare that they have no conflicts of interests.

Acknowledgments

We thank Sabine Maaskant, Willem Turnhout, Raoul Putman, Alain Boersen, Marieke van der Meer and Linda van Hooidonk for their enthusiasm and in Valuable assistance in recruiting, testing the participants of this study and collecting the data.

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