Major Projects

The Role of the HPA Axis in Drug Abuse.

The neurobiology of addiction is the branch of science that concerns itself with the development and maintenance of drug abuse. Among the many puzzling aspects of compulsive drug use (i.e., addiction), lies the fact that although a large number of people experiment with and/or consume drugs, few of them develop an addiction. An increasing body of evidence supports the concept that vulnerability to drug self-administration is altered by, or depends on, hormones of the hypothalamic-pituitary-adrenal (HPA) axis.  Indeed, the fact that vulnerability to drug self-administration in naïve animals, as well as relapse after a drug-free period (also called drug reinstatement), appears to be altered by or depends on hormones of the HPA axis, is supported by the observation that exposure to stress (both physical and psychological) increases or reinstates drug self-administration. The predictability as well as the intensity and duration of a stimulus appear important parameters in inducing this phenomenon. This has led to three major hypotheses: (a) Animals exhibiting a high HPA axis response to (at least some) stressors are more likely to self-administer drugs (i.e., there is a positive correlation between drug vulnerability and stress-induced levels of corticosterone, in particular); (b) Resumed alcohol consumption after a period of abstinence ("relapse") is linked to an attempt to restore a pre-withdrawal level of HPA activity; and (c) Stress can reinstate drug-seeking behavior after a drug-free period. In order to demonstrate whether these hypotheses are correct or not, we need to better understand the mechanisms that modulate long-term changes in HPA axis activity in animals that have been free of alcohol for a period of time, the correlation between individual changes in HPA axis activity caused by drug exposure and by withdrawal/abstinence, and to determine whether these changes are linked to the resumption of drug self-administration. This information can then become key to the development of a sound theory of what leads to drug abuse, including abuse of alcohol.

Dr. George Koob, who directs the Scripps Institute Alcohol Research Center (SIARC), and his colleagues have developed a variety of models of alcohol dependence in rodents. Our laboratory has been part of this Center for over 25 years, which has led to a very fruitful collaboration focused on understanding the influence of alcohol on the HPA axis on one hand, and the role played by this axis in relapse on the other hand. Using the SIARC models, we investigated whether impaired HPA function was associated with alcohol dependence using an animal model in which rats trained to self-administer ethanol exhibit enhanced intake following chronic exposure to alcohol vapor (“dependent” rats) versus trained rats not exposed to alcohol vapor (“non-dependent” rats). Under basal conditions, dependent animals had lower ACTH and corticosterone compared to non-dependent animals.  During self-administration, non-dependent animals displayed ACTH and corticosterone levels elevated in response to alcohol intake.  Dependent animals had attenuated ACTH and corticosterone responses to alcohol intake, indicating that alcohol dependence in our animal model 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.  We are currently determining whether functional changes in the corticotropin releasing factor and/or vasopressin systems underlie the neuroendocrine tolerance observed in these animals.

References

Ji D, Gilpin NW, Richardson HN, Rivier CL and Koob GF 2008 Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats. Behav Pharmacol 19:1-12.