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Alcohol and the HPA Axis

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Alcohol consumption can also act as a stressor

Many people drink alcohol for its anxiety-reducing and stress relieving effects. However, alcohol consumption can also act as a stressor, triggering the body’s stress response system. Research has shown that alcohol can activate and, over time, disrupt the hypothalamic-pituitary-adrenal, or HPA axis.

HPA Axis Stress Response

When a stressor is detected, neurons in the paraventricular nucleus (PVN) of the hypothalamus release hormones called corticotropin-releasing factor (CRF) and vasopressin into the blood vessels connecting the hypothalamus and the pituitary gland. These hormones stimulate the pituitary to make and secrete adrenocorticotropic hormone (ACTH). ACTH causes glucocorticoid synthesis and release from the adrenal glands. Cortisol is the main glucocorticoid in humans, often referred to as “the stress hormone.” Too much stimulation can be harmful to health. Therefore, cortisol eventually signals back to the hypothalamus and pituitary gland to decrease CRF and vasopressin release; this is a negative feedback loop to help modulate the stress response and return the body to homeostasis. Neurotransmitters of the central nervous system (CNS) are also a part of the HPA axis; the neurotransmitter and hormone systems are closely connected to influence many body processes. [2, 6, 13, 16, 17]

Cortisol and CRF

As mentioned above, although many people use alcohol for its relaxing effects, alcohol can act as a stressor to upregulate the HPA axis. Chronic alcohol use, alcohol dependence, and alcohol withdrawal all cause dysregulation of the HPA axis. Altered function of the stress response and related CNS neurotransmitters may result in serious health consequences. [2, 3, 5, 6, 12, 15, 17]

At low and moderate intake, alcohol may reduce, leave unchanged, or increase cortisol levels. [5] Increased alcohol consumption over time can alter the circadian rhythm of cortisol. [2, 5] Initially, cortisol levels are elevated. However, following chronic alcohol exposure, there is often seen a diminished HPA response to stress, as measurements during this time show lower cortisol levels. [2]

CRF activity may become altered through chronic alcohol exposure. Altered CRF function and/or a reduced number of neurons in the PVN of the hypothalamus that release CRF may be responsible for lower cortisol values. Changes in CRF have been associated with withdrawal susceptibility and the capability of stress to cause relapse. [2]

Research has shown that these HPA axis alterations can be long-lasting and difficult, if not impossible, to heal. Additionally, the consequences may be more significant in females, particularly when estrogen levels are low. [2, 5, 15]

Methylation

Alcohol consumption can also affect DNA methylation. Research has shown that alcohol affects two genes that are important in the HPA axis, NR3C1 and FKBP5. These genes become increasingly demethylated with increasing exposure to alcohol. We know that the genes play a role in hormone receptor complexes, including cortisol. Studies have also shown one of these genes (FKBP5), in particular, is associated with PTSD, depression, and anxiety. [7]

Norepinephrine and Dopamine

Alcohol consumption, as well as other drugs, stress, and anxiety, can influence dopamine and norepinephrine activity in the nucleus accumbens (NAc), part of the brain’s reward system. [10] Alcohol can increase both dopamine and taurine levels in the NAc; taurine participates in activating the reward system and dopamine release. Disturbances in the reward system are an underlying issue in people with alcohol dependence. [8]

Serotonin

Research has also shown that alcohol may cause an increase in tryptophan in the hippocampus, serotonin in the hippocampus and amygdala, and serotonin turnover. On the other hand, withdrawal from alcohol may decrease tryptophan, serotonin, and serotonin turnover. This may lead to difficulty in modulating corticosteroid levels, resulting in low mood, as well as other withdrawal signs and symptoms. [1]

GABA and Glutamate

Studies have shown that both acute and chronic alcohol consumption can increase GABAergic transmission and alter GABA synapses in the central amygdala. [14]

Acute alcohol intake can enhance inhibitory neurotransmission through GABAa receptors, which are found in 40% of the synapses in the brain. This leads to an overall increased functional connectivity in the brain. [11] Over time, however, the brain will try to restore balance. Chronic alcohol intake may change the GABAa receptors, leading to reduced GABA receptor function. The altered GABA receptor function may be related to alcohol sensitivity, tolerance, and dependence. [9] While short-term alcohol intake increases the brain’s functional connectivity, the functional connectivity is lowered in chronic alcohol consumption. [11]

Alcohol increases GABA to limit excitatory neurotransmission, particularly through GABA inhibiting the excitatory neurotransmitter glutamate. Following chronic alcohol exposure with reduced GABA function, glutamate levels may increase without GABA’s inhibitory effect. Higher glutamate levels may be partially responsible for some withdrawal symptoms. This increase of glutamate and its consequential effects have been shown to continue two weeks into abstinence [4, 14]

HPA axis balance is essential for optimal wellness, from sleep to the stress response, mood to cognitive function, and more. Each person’s HPA axis – as understood through the individual’s symptoms, lifestyle factors, and laboratory measurements such as hormones and neurotransmitters – is a reflection of their health. Alcohol consumption, whether chronic or acute, can alter the HPA axis, contributing to a variety of health concerns. If you’re a heavy drinker, recovering from chronic alcohol use, or even have just one drink on occasions, monitoring and modulating HPA axis function may help you and your healthcare practitioner understand and address imbalances and health concerns, preparing your way for a healthier future!

 

Resources

1. Ara, I., & Bano, S. (2015). Serotonergic activity and hypothalamic-pituitary-adrenal axis response in alcohol administered and subsequently withdrawn rats. Pak. J. Pharm. Sci, 28(4), 1259-1265.

2. Becker, H. C., & Happel, K. I. (2012). Effects of alcohol dependence and withdrawal on stress responsiveness and alcohol consumption. Alcohol Research-Current Reviews, 34(4), 448.

3. Boschloo, L., Vogelzangs, N., Licht, C. M., Vreeburg, S. A., Smit, J. H., van den Brink, W., … & Penninx, B. W. (2011). Heavy alcohol use, rather than alcohol dependence, is associated with dysregulation of the hypothalamic–pituitary–adrenal axis and the autonomic nervous system. Drug and alcohol dependence, 116(1), 170-176.

4. Brousse, G., Arnaud, B., Vorspan, F., Richard, D., Dissard, A., Dubois, M., … & Sapin, V. (2012). Alteration of glutamate/GABA balance during acute alcohol withdrawal in emergency department: a prospective analysis. Alcohol and alcoholism, 47(5), 501-508.

5. Čupić, Ž., Stanojević, A., Marković, V. M., Kolar‐Anić, L., Terenius, L., & Vukojević, V. (2016). The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations. Addiction biology.

6. Dai, X., Thavundayil, J., & Gianoulakis, C. (2002). Response of the hypothalamic-pituitary-adrenal axis to stress in the absence and presence of ethanol in subjects at high and low risk of alcoholism. Neuropsychopharmacology, 27(3), 442-452.

7. Dogan, M. V., Lei, M. K., Beach, S. R., Brody, G. H., & Philibert, R. A. (2016). Alcohol and tobacco consumption alter hypothalamic pituitary adrenal axis DNA methylation. Psychoneuroendocrinology, 66, 176-184.

8. Ericson, M., Chau, P., Clarke, R. B., Adermark, L., & Söderpalm, B. (2011). Rising taurine and ethanol concentrations in nucleus accumbens interact to produce dopamine release after ethanol administration. Addiction biology, 16(3), 377-385.

9. Follesa, P., Biggio, F., Talani, G., Murru, L., Serra, M., Sanna, E., & Biggio, G. (2006). Neurosteroids, GABAA receptors, and ethanol dependence. Psychopharmacology, 186(3), 267-280.

10. Karkhanis, A. N., Locke, J. L., McCool, B. A., Weiner, J. L., & Jones, S. R. (2014). Social isolation rearing increases nucleus accumbens dopamine and norepinephrine responses to acute ethanol in adulthood. Alcoholism: Clinical and Experimental Research, 38(11), 2770-2779.

11. Lithari, C., Klados, M. A., Pappas, C., Albani, M., Kapoukranidou, D., Kovatsi, L., … & Papadelis, C. L. (2012). Alcohol affects the brain’s resting-state network in social drinkers. PloS one, 7(10), e48641.

12. Mick, I., Spring, K., Uhr, M., & Zimmermann, U. S. (2013). Alcohol administration attenuates hypothalamic–pituitary–adrenal (HPA) activity in healthy men at low genetic risk for alcoholism, but not in high‐risk subjects. Addiction biology, 18(5), 863-871.

13. Randall, M. (2010). The physiology of stress: Cortisol and the hypothalamic-pituitary-adrenal axis. DUJS Online–The Darmouth Undergraduate Journal of Science. Fall.

14. Roberto, M., Gilpin, N. W., & Siggins, G. R. (2012). The central amygdala and alcohol: role of γ-aminobutyric acid, glutamate, and neuropeptides. Cold Spring Harbor perspectives in medicine, 2(12), a012195.

15. Silva, S. M., & Madeira, M. D. (2012). Effects of chronic alcohol consumption and withdrawal on the response of the male and female hypothalamic–pituitary–adrenal axis to acute immune stress. Brain research, 1444, 27-37.

16. Spencer, R. L., & Hutchison, K. E. (1999). Alcohol, aging, and the stress response. Alcohol Research and Health, 23(4), 272-283.

17. Stephens, M. A. C., & Wand, G. (2012). Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Research-Current Reviews, 34(4), 468.

 

Clinical Contributor

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Connie Shoemaker, ND

Connie Shoemaker, ND

“Educating Sanesco’s clients is the culmination of a life’s work.” Beginning when she left the hospital environment to manage a functional laboratory, Genova Diagnostics (formerly Great Smokies Laboratories) in 1987, Dr. Connie Shoemaker has continued to increase her knowledge of herbs and biochemistry as a journey of love. With her bachelor’s in science from Western Carolina University, she had worked in hospital laboratories for the first twelve years of her career. Then, personal health challenges led her to discover a new approach to her health and a determination to share it with others. In 1991, she began teaching and educating innovative practitioners in the U.S. and internationally as a manager of marketing, sales, and customer service.

The addition of her Doctor of Naturopathy degree to her existing knowledge base expanded her knowledge and her respect for a more natural approach to healing through balance. At Sanesco, she initially served to oversee technical development of products and services.

Now, she educates Sanesco’s clients on application of the CSM™ model for their specific patients and how to integrate the CSM™ model with other modalities they offer in their practice. In her personal life, Connie educates private clients on various health topics.

Disclaimer: The information provided is only intended to be general educational information to the public. It does not constitute medical advice. If you have specific questions about any medical matter or if you are suffering from any medical condition, you should consult your doctor or other professional healthcare provider.

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