Adolescent drinking has been linked to increased alcohol abuse in adults. Despite the high societal cost of this phenomenon, the mechanisms responsible for it remain mostly unknown. In view of the importance of the hypothalamic-pituitary-adrenal (HPA) axis in alcohol abuse and relapse per se, as well as in affective disorders thought to be linked to abuse/relapse, we propose to test the hypothesis that alcohol exposure during adolescence, in a model called Adolescent Intermittent Alcohol (AIE), alters the adult rat's HPA axis activity. Currently, there is no available detailed information regarding the time-course over which alcohol upregulates parameters of the HPA axis in adolescent rats, or the magnitude of this response. However, this information is critical for the development of the AIE model. We will first explore the ability of intermittent alcohol vapors to activate the HPA axis in male and female rats. Parameters measured will include plasma ACTH levels, c-fos signaling as an index of neuronal activation of corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN) of the hypothalamus, and PVN CRF gene expression. Particular emphasis will be put on the potential presence of sexual dimorphism in HPA axis activity. As both humans and outbred rodents often fall into a low- or a high-responder group regarding a variety of stress-induced responses, and as this may have important consequences for the long-term consequences of AIE, we will also determine whether we can identify these two groups in our model. If we identify low- and high-responders, we will then test the hypothesis that these differential HPA axis responses to AIE correspond to similar differences in adults. We will then explore the mechanisms through which AIE alters the adult rats'HPA axis. We recently observed that alcohol upregulates hypothalamic and brain stem catecholaminergic circuits, and that this (nor)adrenergic activation plays an important role in mediating the rat HPA axis response to alcohol. We will therefore focus on the hypothesis that the brain catecholaminergic circuitry of adult rats exposed to AIE, differs from that of control animals;that the ability of (nor)epinephrine, which is released by alcohol in the brain, to activate the HPA axis, is also altered by AIE;and that the role played by catecholamines in modulating the consequences of AIE might be sexually dimorphic. Collectively, these results will provide novel and important information regarding the long-term influence of adolescent alcohol exposure on the adult HPA axis. This will then pave the way for future correlative studies that explore potential functional links between adult alcohol self-administration induced by pubertal exposure to the drug, and HPA axis activity.

Public Health Relevance

This Project tests the hypothesis that in the rat, exposure to alcohol during adolescence induces long-term changes in the hypothalamic-pituitary-activity of the adults, with emphasis on the possible presence of sexual dimorphism. This will pave the way for future experiments that investigate functional links between this adult altered endocrine activity and the increased alcohol abuse known to take place in adults exposed to alcohol when juvenile.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-DD (11))
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Bechtholt-Gompf, Anita
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Salk Institute for Biological Studies
La Jolla
United States
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Boutros, Nathalie; Der-Avakian, Andre; Kesby, James P et al. (2018) Effects of adolescent alcohol exposure on stress-induced reward deficits, brain CRF, monoamines and glutamate in adult rats. Psychopharmacology (Berl) 235:737-747
Allen, Camryn D; Grigoleit, Jan-Sebastian; Hong, Joonho et al. (2016) Exposure to alcohol during adolescence exerts long-term effects on stress response and the adult brain stress circuits. Neuroscience 339:64-71
Boutros, Nathalie; Der-Avakian, Andre; Semenova, Svetlana et al. (2016) Risky choice and brain CRF after adolescent ethanol vapor exposure and social stress in adulthood. Behav Brain Res 311:160-166
Logrip, M L; Rivier, C; Lau, C et al. (2013) Adolescent alcohol exposure alters the rat adult hypothalamic-pituitary-adrenal axis responsiveness in a sex-specific manner. Neuroscience 235:174-86
Allen, Camryn D; Lee, Soon; Koob, George F et al. (2011) Immediate and prolonged effects of alcohol exposure on the activity of the hypothalamic-pituitary-adrenal axis in adult and adolescent rats. Brain Behav Immun 25 Suppl 1:S50-60
Allen, C D; Rivier, C L; Lee, S Y (2011) Adolescent alcohol exposure alters the central brain circuits known to regulate the stress response. Neuroscience 182:162-8