Features of neurosteroid support of the state of alcohol dependence and its correction with dosed physical load in rats

  • A. M. Titkova Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine
  • O. G. Berchenko Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine
  • O. V. Veselovska Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine
  • A. V. Shliakhova Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine
Keywords: steroid hormones; electrical activity; brain; alcohol withdrawal; running wheel; rats.


The role of steroid hormones in regulation of the functions of the emotiogenic limbic-neocortical system has been actively studied over the recent decades in order to determine their synthesis in the brain structures and role in the development and maintenance of dependence on psychoactive substances. However, the wide range of neurosteroids and their metabolites, as well as structural specific features of the synthesis of both neurohormones and their receptors make it difficult to obtain experimental data and interpret the results of the study. The participation of progesterone, cortisol, testosterone and estradiol in the development of alcohol dependence and the changes in their concentrations in the hypothalamus, hippocampus, amygdala and serum under the influence of dosed physical load were studied in 48 outbred adult male rats. Alcohol dependence was modeled by means of consuming food containing alcohol in the dose of 1.25 g of ethanol per 1 kg of rat body weight for two months. Dosed physical load was reproduced by a rat running in a wheel for 30 minutes daily for 7–10 days against the background of alcohol withdrawal. Neuroethological testing of craving for alcohol, EEG recording of the neocortex, hippocampus and amygdala was performed using a computer-diagnostic complex. The concentration of steroid hormones was determined in the structures of the brain and blood serum by the enzyme-linked immunosorbent assay. It was shown that dosed physical load attenuated the alcohol motivation of rats. On the 5th day it suppressed the electrographic manifestations of paroxysmal activity in the hippocampus and increased the level of the theta-rhythm in the amygdala, and on the 7th day it activated the neocortex with increasing beta-rhythm. This effect was accompanied by an increase in serum testosterone level against the background of maintaining functional tension of the peripheral glucocorticoid link of the hypothalamus-pituitary-adrenal system, which was observed in a state of alcohol dependence. The study demonstrated that progesterone plays the key role in allostatic rearrangements of the functional state of animals. An imbalance of progesterone levels was revealed in the brain structures: an increase – in the hypothalamus and hippocampus, and a decrease – in the amygdala under alcohol dependence; a decrease – in the hippocampus with recovery in the amygdala against the background of its high level in the hypothalamus, which occurs under the influence of dosed physical load on the rats under alcohol withdrawal. Thus, the dosed physical load is a promising approach to alcohol dependence rehabilitation.


Berchenco, O. G., Titkova, A. M., Veselovs’ka, O. V., Shlakhova, A. V., Levicheva, N. O., & Prichod’ko, O. O. (2017). Electrical activity of the cerebral structures and regulatory effects of NO, steroid hormones, and BDNF in rats with experimental alcohol addiction. Neurophysiology, 4(3), 240–242.

Bowen, R. S., Knab, A. M., Hamilton, A. T., McCall, J. R., Moore-Harrison, T. L., & Lightfoot, J. T. (2012). Effects of supraphysiological doses of sex steroids on wheel running activity in mice. Journal Steroids Hormonal Science, 3(2), 110–121.

Brager, A. J., & Hammer, S. B. (2012). Impact of wheel running on chronic ethanol intake in aged Syrian hamsters. Physiology and Behavior, 107(3), 418–423.

Buresh, Y., Petran, M, & Zakhar, I. (1962). Elektro-fiziologicheskiye metody issledovaniya [Electro-physiological research methods]. Izdatelstvo Inostrannoj Literatury, Moscow (in Russian).

Caldwell, J. D., Gao, G., Frasch, M., Jirikowski, G. F., & Witt, D. M. (2001). Testosterone alters membrane binding of progesterone in male rat brains. European Journal of Anatomy, 5(1), 37–45.

Carroll, B. J., & Heath, D. B. (1975). Corticosteroids in brain tissue. Endocrinology, 97, 290–300.

Chapman, K., Holmes, M., & Seckl, J. (2013). 11β-Hydroxysteroid dehydrogenases: Intracellular gate-keepers of tissue glucocorticoid action. Physiological Reviews, 93(3), 1139–1206.

Ciocca, G., Limoncin, E., Carosa, E., Sante S. D., Gravina, G. L., Mollaioli, D., Gianfrilli, D., Lenzi, A., & Jannini, E. A. (2016). Is testosterone a food for the brain? Sexual Medicine Reviews, 4(1), 15–25.

Cooke, B. M. (2006). Steroid-dependent plasticity in the medial amygdale. Neuroscience, 138(3), 997–1005.

Costardi, J. V., Nampo, R. A., Silva, G. L., Ribeiro, M. A., Stella, H. J., Stella, M. B., & Malheiros, S. V. (2015). A review on alcohol: from the central action mechanism to chemical dependency. Revista da Associação Médica Brasileira, 61(4), 381–387.

Ehringer, M. A., Hoft, N. R., & Zunhammer, M. (2009). Reduced alcohol consumption in mice with access to a running wheel. Alcohol, 43(6), 443–452.

Galperin, S. I., & Tatarskij, N. E. (1967). Metodiki issledovaniya vysshej nervnoj deyatel’nosti cheloveka i zhivotnykh [Research methods of higher nervous activity of humans and animals]. Vysshaya Shkola, Moscow (in Russian).

Gjerstad, J. K., Lightman, S. L., & Spiga, F. (2018). Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility. Stress, 21(5), 403–416.

Gong, S., Miao, Y.-L., Jiao, G.-Z., Sun, M.-J., Li, H., Lin, J., Luo, M. J., & Taning, H. J. (2015). Dynamics and correlation of serum cortisol and corticosterone under different physiological or stressful conditions in mice. PLoS One, 10(2), e0117503.

Harlan, B. A., Becker, H. C., Woodward, J. J., & Riegel, A. C. (2018). Opposing actions of CRF-R1 and CB1 receptors on VTA GABAergic plasticity following chronic exposure to ethanol. Neuropsychopharmacology, 43, 2064–2074.

Huang, Y., Mohan, A., De Ridder, D., Sunaert, S., & Vanneste, S. (2018). The neural correlates of the unified percept of alcohol-related craving: A fMRI and EEG study. Scientific Reports, 8, 923–934.

Keiflin, R., & Janak, H. (2015). Dopamine prediction errors in reward learning and addiction: From theory to neural circuitry. Neuron, 88(2), 247–263.

Koob, G. F. (2013). Theoretical frameworks and mechanistic aspects of alcohol addiction: Alcohol addiction as a reward deficit disorder. Current Topics in Behavioral Neurosciences, 13, 3–30.

Koob, G. F., Buck, C. L., Cohen, A., Edwards, S., Park, P. E., Schlosburg, J. E., Schmeichel, B., Vendruscolo, L. F., Wade, C. L., Whitfield Jr., T. W., & George, O. (2014). Addiction as a stress surfeit disorder. Neuropharmacology, 76, 370–382.

Lenz, B., Muller, C. P., Stoessel, C., Sperling, W., Biermann, T., Hillemacher, T., Bleich, S., & Kornhuber, J. (2012). Sex hormone activity in alcohol addiction: Integrating organizational and activational effects. Progress in Neurobiology, 96, 136–163.

Mellon, S. H., Griffin, L. D., & Compagnone, N. A. (2001). Biosynthesis and action of neurosteroids. Brain Research Reviews, 37, 3–12.

Mons, N., & Beracochea, D. (2016). Behavioral neuroadaptation to alcohol: From glucocorticoids to histone acetylation. Frontiers in Psychiatry, 7, 165–173.

Osterlund, C. D., Rodriguez-Santiago, M., Woodruff, E. R., Newsom, R. J., Chadayammuri, A. P., & Spencer, R. L. (2016). Glucocorticoid fast feedback inhibition of stress-induced ACTH secretion in the male rat: rate independence and stress-state resistance. Endocrinology, 157(7), 2785–2798.

Peltier, M. R., & Sofuoglu, M. (2018). The role of exogenous progesterone in the treatment of males and females with substance use disorders: A narrative review. CNS Drugs, 32(5), 421–435.

Peters, S., Jolles, D. J., Van Duijvenvoorde, A. C., Crone, E. A., & Peper, J. S. (2015). The link between testosterone and amygdala-orbitofrontal cortex connectivity in adolescent alcohol use. Psychoneuroendocrinology, 53, 117–126.

Ritsner, M. S., & Weizman, A. (2008). Neuroactive steroids in brain function, behavior and neuropsychiatric disorders: Novel strategies for research and treatment. Springer.

Rose, A. K., Shaw, S. G., Prendergast, M. A., & Little, H. J. (2010). The importance of glucocorticoids in alcohol dependence and neurotoxicity. Alcoholism: Clinical and Experimental Research, 34(12), 2011–2018.

Samidurai, M., Kang, H., Ramasamy, V. S., & Jo, J. (2018). Impact of electrical stimulation on cortisol secretion in rat adrenal gland. Biochip Journal, 12, 216–221.

Seo, J. H. (2018). Treadmill exercise relieves stress-induced anxiety behavior in rats. Journal of Exercise Rehabilitation, 14(5), 724–730.

Taves, M. D., Ma, C., Heimovics, S. A., Saldanha, C. J., & Soma, K. K. (2011). Measurement of steroid concentrations in brain tissue: Methodological considerations. Frontiers in Endocrinologi (Lausanne), 2, 1–13.

Titkova, A. M., Berchenko, O. G., Shlyahova, A. V., Veselovskaya, E. V., & Prihodko, E. A. (2018). Vzaimodejstvija dofamina, oksida azota i testosterona v mozgovoj sisteme motivacionnogo podkreplenija krys s alkogolnoj zavisimostju i pod vlijaniem donatora oksida azota [Interaction of dopamine, nitric oxide and testosterone in the brain system of motivational reinforcement in rats with alcohol dependence and under nitric oxide donator impact]. The Journal of V. N. Karazin Kharkiv National University, Series Biology, 30, 92–98.

Veselovska, O. V., Shliakhova, A. V., Berchenko, O. G., & Titkova, A. M. (2020). Neuroadaptation in the system of emotional reinforcement under alcohol dependence. Ukrainskyi Visnyk Psykhonevrolohii, 28(3), 22–25 (in Ukrainian).

Walker, J. J., Spiga, F., Gupta, R., Zhao, Z., Lightman, S. L., & Terry, J. R. (2015). Rapid intra-adrenal feedback regulation of glucocorticoid synthesis. Journal of the Royal Society, Interface the Royal Society, 12, 20140875.

Zlebnik, N. E., Saykao, A. T., & Carroll, M. E. (2014). Effects of combined exercise and progesterone treatments on cocaine seeking in male and female rats. Psychopharmacology, 231(18), 3787–3798.

How to Cite
Titkova, A. M., Berchenko, O. G., Veselovska, O. V., & Shliakhova, A. V. (2020). Features of neurosteroid support of the state of alcohol dependence and its correction with dosed physical load in rats . Regulatory Mechanisms in Biosystems, 11(4), 546-551. https://doi.org/10.15421/022084