Women who abuse alcohol are twice as likely to develop anxiety disorders compared with men, a phenomenon in which the underlying biological mechanisms are unknown. Our overall objective is to identify the interactive effects of alcohol and estrogen on arginine vasopressin (AVP), a well-established key molecular mediator of anxiety, in order to elucidate the molecular mechanisms predisposing women to increased risk of anxiety disorders. Adolescent binge drinking is a potential risk factor for the development of adult anxiety disorders due to the heightened stress reactivity that occurs as a direct result of increased circulating estrogens during pubertal development. Little is known about the long-term neurobiological consequences of alcohol consumption during puberty, which is a dynamic and important period of brain development that involves changes in cortical gray matter, synaptic connectivity, and increased neurogenesis. Exposure of alcohol during this critical period of extensive brain remodeling may result in permanent neuronal damage or disruptions in the formation of new neuronal connections, which might manifest as adult behavioral psychoses, including anxiety disorder. Our preliminary data show that 1) alcohol exposure during puberty increased AVP gene expression in specific regions of the brain. Therefore, the experiments proposed in Specific Aim 1 will directly test the hypotheses that there is a critical window of time during pubertal development when the AVP system is most vulnerable to the effects of alcohol and (2) that estrogen exacerbates the effects of alcohol on AVP gene expression. Also, our preliminary data demonstrate that alcohol treatment and estrogen receptor ligands increased AVP gene expression in neuronal cells derived from the hypothalamus, and gene expression is closely correlated with the activity of the gene promoter. Alcohol also activates estrogen-signaling pathways in the brain, which suggests that the underlying mechanisms for alcohol-induced changes in AVP may be mediated by estrogen signaling pathways. Therefore, the experiments proposed in Specific Aim 2 will directly test the hypotheses that (1) acute alcohol exposure increases AVP promoter activity in neuronal cells, (2) that there are specific regulatory regions of the AVP promoter that interact with alcohol, and (3) that estrogen and alcohol interact synergistically to increase AVP promoter activity. To date, specific molecular and neuroendocrine markers that are activated by alcohol during puberty have not been identified. This proposal is focused on a specific candidate gene (AVP) and its downstream signaling pathways that are developmentally shaped during puberty. We expect these studies to show that AVP is permanently altered, either as a direct target for alcohol or indirectly through steroid hormone receptor signaling pathways. Thus, the value of this research lies in the potential for therapeutic approaches that would target specific genes and perhaps reverse brain damage caused by alcohol consumption during pubertal development as well as strengthen reasons for abstaining from alcohol during that time.

Public Health Relevance

Women who abuse alcohol are twice as likely to develop anxiety disorders compared with men, a phenomenon in which the underlying biological mechanisms are unknown. This proposal is focused on a specific candidate gene (AVP) and its downstream signaling pathways that are developmentally shaped during puberty. We expect these studies to show that AVP is permanently altered, either as a direct target for alcohol or indirectly through steroid hormone receptor signaling pathways. Thus, the value of this research lies in the potential for therapeutic approaches that would target specific genes and perhaps reverse brain damage caused by alcohol consumption during pubertal development as well as strengthen reasons for abstaining from alcohol during that time.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA018398-02
Application #
7934536
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grandison, Lindsey
Project Start
2009-09-20
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$186,875
Indirect Cost
Name
Loyola University Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Prins, Sarah A; Przybycien-Szymanska, Magdalena M; Rao, Yathindar S et al. (2014) Long-term effects of peripubertal binge EtOH exposure on hippocampal microRNA expression in the rat. PLoS One 9:e83166
Tajuddin, Nuzhath F; Przybycien-Szymanska, Magdalena M; Pak, Toni R et al. (2013) Effect of repetitive daily ethanol intoxication on adult rat brain: significant changes in phospholipase A2 enzyme levels in association with increased PARP-1 indicate neuroinflammatory pathway activation. Alcohol 47:39-45
Przybycien-Szymanska, Magdalena M; Gillespie, Roberta A; Pak, Toni R (2012) 17?-Estradiol is required for the sexually dimorphic effects of repeated binge-pattern alcohol exposure on the HPA axis during adolescence. PLoS One 7:e32263
Przybycien-Szymanska, Magdalena M; Mott, Natasha N; Paul, Caitlin R et al. (2011) Binge-pattern alcohol exposure during puberty induces long-term changes in HPA axis reactivity. PLoS One 6:e18350
Przybycien-Szymanska, Magdalena M; Mott, Natasha N; Pak, Toni R (2011) Alcohol dysregulates corticotropin-releasing-hormone (CRH) promoter activity by interfering with the negative glucocorticoid response element (nGRE). PLoS One 6:e26647
Przybycien-Szymanska, Magdalena M; Rao, Yathindar S; Pak, Toni R (2010) Binge-pattern alcohol exposure during puberty induces sexually dimorphic changes in genes regulating the HPA axis. Am J Physiol Endocrinol Metab 298:E320-8