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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA019973-04
Application #
8520117
Study Section
Special Emphasis Panel (ZAA1-DD (11))
Program Officer
Bechtholt-Gompf, Anita
Project Start
2010-09-05
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$395,423
Indirect Cost
$187,852
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037