Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Alcohol-Dependent Self-Administering Rats
H. Richardson1, 3; L. E. O’Dell2; S. Y. Lee3; G. F. Koob1; C. L. Rivier3
1. Neuropharmacology, CVN-7, The Scripps Research Institute, La Jolla, CA, USA.
2. Psychology, University of Texas, El Paso, El Paso, TX, USA.
3. Clayton Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA, USA.
Alcohol is a potent modulator of the stress system, and dysregulation of the stress axis may contribute to the development of alcohol abuse and alcoholism. Experimenter-controlled injection of alcohol has been shown to stimulate the hypothalamic-pituitary-adrenal (HPA) axis in rats, and the HPA response is blunted in animals previously exposed to chronic alcohol.
To test the hypothesis that impaired HPA function is associated with alcohol dependence; an animal model in which rats trained to self-administer ethanol was used. Wistar rats exhibited enhanced intake following chronic exposure to alcohol vapor (“dependent” rats) compared to trained rats not exposed to alcohol vapor (“non-dependent” rats). Serial blood samples were obtained via indwelling jugular catheters just prior to, during, and following oral self-administration of alcohol for measurement of plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone.
Under basal conditions, dependent animals had lower ACTH and corticosterone compared to non-dependent animals. During self-administration, non-dependent animals displayed elevated ACTH and corticosterone levels in response to alcohol intake. Dependent animals had attenuated ACTH and corticosterone responses to alcohol intake, indicating that alcohol dependence is associated with dysregulation of the HPA axis.
These data suggest that a dampened neuroendocrine state in dependent animals may lead to excessive drinking in order to establish normal endocrine function. Whether functional changes in the corticotropin-releasing factor system underlie the neuroendocrine tolerance observed in these animals is currently under investigation.