Stress-induced change in serum BDNF is related to quantitative family history of alcohol use disorder and age at first alcohol use
Introduction
This study examined the relationships between brain-derived neurotrophic factor (BDNF), stress and alcohol consumption in a population of healthy social drinkers. BDNF is a secreted protein that is important for neuronal survival, differentiation and synaptic plasticity (Binder and Scharfman, 2004, Thoenen, 1995). A growing body of research suggests that BDNF may also play a role in alcohol consumption. The most compelling evidence has come from animal models. These studies suggest a cycle in which chronic heavy alcohol exposure leads to long-lasting dose-dependent reduction of BDNF in areas of the brain such as the medial prefrontal cortex, and lower BDNF is then associated with heightened alcohol intake (Darcq et al., 2015, Logrip et al., 2015). Further, exposure to stress or anxiety-provoking stimuli influences expression and intracellular trafficking of the BDNF protein (Hosang et al., 2014). Both intense acute and chronic negative stress have been associated with significant down-regulation of both BDNF mRNA and BDNF protein levels in brain areas such as the hippocampus (Lee et al., 2008, Murakami et al., 2005, Nair et al., 2007, Rothman et al., 2012, Smith et al., 1995, Tsankova et al., 2006, Ueyama et al., 1997, Yu et al., 2012). Taken together, studies in animal models suggest that negative stress-related changes in BDNF signaling could increase risk for both anxiety and alcohol misuse (see Maletic et al., 2007).
However, existing studies of the relationships between BDNF protein, stress and alcohol consumption in humans have yielded mixed results. Both positive and negative correlations between alcohol-related factors and peripheral BDNF protein levels have been observed (Heberlein et al., 2010, Huang et al., 2008, Joe et al., 2007, Meng et al., 2011). These heterogeneous findings may have occurred in part because human studies have been limited to the measurement of changes in peripheral BDNF protein levels in serum or plasma, which are not as well understood as those in the central nervous system (Karege et al., 2005). Further, only one other study (Meng et al., 2011) has examined serum BDNF before and after acute stress (public speaking and math stressor). This study included a small group of males with (n = 14) and without (n = 10) alcohol use disorder (AUD). Control participants with a positive family history of AUD were excluded, and the researchers did not control for polymorphisms of the BDNF gene in their participants. Meng et al. (2011) found that stress caused an increase in both BDNF and cortisol with no differences between the AUD group and controls. Stress-related changes in BDNF and cortisol were not correlated in their study, suggesting that BDNF regulatory mechanisms may differ from those of the hypothalamic-pituitary-adrenal (HPA) axis (Meng et al., 2011).
The current study extends the work of Meng et al. (2011). Our primary aim was to examine the within-subjects effect of acute stress on serum BDNF levels (ΔBDNF) in healthy male and female social drinkers. As a secondary consideration, we explored which heritable factors (e.g., quantitative family history of alcohol use disorder) and environmental factors (e.g., early initiation of alcohol consumption) exerted the greatest influences on ΔBDNF in our limited sample. Importantly, although not the focus of our study, all of our statistical analyses accounted for the presence versus absence of the BDNF Val66Met polymorphism (rs6265). This polymorphism, which influences neuronal activity-dependent release of BDNF protein (Egan et al., 2003), has often been discounted in studies of peripheral BDNF levels in human participants.
Section snippets
Materials and methods
This study was approved by the Texas State University Institutional Review Board, and research was performed in accordance with ethical standards of the Declaration of Helsinki. All participants provided written, informed consent.
Demograhics and alcohol use
Characteristics of the participant sample and statistical outcomes are presented in Table 2. Genotype groups did not differ significantly on age, parental education, trait anxiety, past-month perceived stress, or distribution of gender, ethnicity, and race. Alcohol use variables, including age at first drink and first intoxication, QFI, days since last drink, and qFH were also statistically similar in the two genotype groups.
Subjective response to stressor
In the entire sample, the acute stressor significantly increased
Discussion
Although the role of BDNF in anxiety-modulated alcohol consumption has been documented extensively using animal models (Logrip et al., 2015), few studies have examined the relationship between alcohol use and BDNF stress-reactivity in humans. The current study is unique in that serum BDNF levels were examined before and after acute stress in social drinkers with and without the BDNF Val66Met polymorphism. Importantly, genotype groups were statistically similar on demographics and other relevant
Conclusions
Alcohol consumption is a complex, multifactorial phenomenon. Although the inter-relationships of BDNF, stress, and alcohol use are becoming clear in the animal literature, additional research is needed in human populations. The current study provides an important step in that direction. Taken together, our findings support the notion that heritable factors interact with environmental influences to impact the characteristics of ΔBDNF. Family history of alcohol use disorder and age of first
Acknowledgements
This study was supported by the John P. McGovern Fellowship from the Texas Research Society on Alcoholism and a research fellowship from the Graduate College at Texas State University to Shobhit Sharma (Natalie Ceballos, faculty sponsor). Special thanks to Mr. John Treffalls and Ms. Jaime Chambers for their assistance with the project.
References (52)
- et al.
Stress modulation of visuomotor binding
Neuropsychologia
(2008) - et al.
BDNF Val66Met polymorphism is associated with higher anticipatory cortisol stress response, anxiety, and alcohol consumption in healthy adults
Psychoneuroendocrinology
(2011) - et al.
Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations
Am. J. Hum. Genet.
(2004) - et al.
The BDNF Val66Met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function
Cell
(2003) - et al.
Candidate and non-candidate genes in behavior genetics
Curr. Opin. Neurobiol.
(2013) - et al.
Meta-analysis of six genes (BDNF, DRD1, DRD3, DRD4, GRIN2B, MAOA) involved in neuroplasticity and the risk for alcohol dependence
Drug Alcohol Depend.
(2015) - et al.
BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2010) - et al.
Cerebellum volume in high-risk offspring from multiplex alcohol dependence families: association with allelic variation in GABRA2 and BDNF
Psychiatry Res. Neuroimaging
(2011) - et al.
Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity
Biol. Psychiatry
(2005) - et al.
Allowing animals to bite reverses the effects of immobilization stress on hippocampal neurotrophin expression
Brain Res.
(2008)