Medical Student Research Fellowship for Summer 2009
Mentor: Bryon Adinoff, M.D.
Room number: FL500, Bass Center
Mail Code: 8564
Phone number: 214-645-6975
Project title: Stress, HPA Axis Dysfunction, and Relapse in Alcoholism (NIAAA)
Human subjects IRB approved project number (where applicable): 12007-023
Animal subjects IRB approved project number (where applicable):
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Patient-based research
Brief Description of Project:
Abstract of Funded Project: Stress has long been considered to increase relapse vulnerability, although the definitive supportive study is lacking. In addition, a neurobiologic mechanism accounting for stress-induced relapse remains tentative, although the hypothalamic-pituitary-adrenal (HPA) is often posited as a key link. The HPA axis provides a regulatory feedback network between the brain and the body's behavioral and physiologic responses to stress, recovery, and adaptation. Both trauma and chronic alcohol use produce persistent disturbances in the HPA axis response to stress. Suppression of adrenocortical glucocorticoid release, in particular, is identified as a key component of this altered stress response. The chronic use of alcohol may also impair the stress-induced release of neurosteroids, compounds that directly modulate GABAergic activity. Thus, diminished glucocorticoid and neurosteroid responsiveness during abstinence may impair the central nervous system's (CNS) ability to mount an appropriate response to environmental stressors, thus heightening the probability of relapse. In the proposed study, the investigators will expand upon their extensive work on stress, HPA axis disturbances, and substance use disorders to directly assess the contribution of trauma, stress, and alcohol use upon pituitary-adrenocortical functioning in alcohol-dependent subjects. The relative contribution of adrenocortical disruption and episodic stress to drinking behavior will then be prospectively determined over the next six months.
Hypothesis: We hypothesize (1) that lifetime trauma, recent stress, and chronic alcohol use will additively contribute to adrenocortical hyposensitivity, (2) attenuated glucocorticoid and neurosteroid release and increased episodic stress will additively predict a return to drinking. Genotyping and linkage analysis will also be obtained, as well as measures of personality, will also be obtained.
Methods: One hundred treatment-seeking, one-month abstinent, alcohol-dependent subjects will be studied. Standardized assessments will be used to assess childhood, adolescent, and adult trauma as well as recent (six months) stress. Pituitary-adrenal (including ACTH, cortisol, and neurostoids) provocation to both neuroendocrine (ovine corticotropin releasing hormone, oCRH, and cosyntropin) and experiential (public speaking) challenges will be assessed. Drinking behavior will be determined for six months following the initial assessment.
Significance: If our hypothesis are proven correct, a definitive connection between previous trauma and ongoing stress upon relapse risk will be demonstrated. The identification of a specific biologic mechanism that underlies this association will provide a fertile framework for the development of pharmacological interventions to decrease relapse in this vulnerable population.
Specific Project of Medical Student:
In addition to measures of ACTH, cortisol, and neurosteroids described above, we are also measuring the response of norepinephrine, neuropeptide Y, vasopressin and BDNF to oCRH infusion and/or public speaking stress. The MS will be responsible for conducting a literature review of these hormones and develop a background rationale and hypotheses for predicted differences in these transmitters in alcohol-dependent subjects relative to controls. Following an analysis of the data, a written explanation of the outcomes will be written. The MS will meet with Dr. Adinoff at least weekly for supervision. In addition, the MS will assist research assistants and physicians in screening and assessment for ongoing laboratory studies appropriate for her/his training. The MS will be expected to have a good sense of clinical laboratory research in substance abuse by the end of their rotation.
Previous Research Activities or Publications with Medical Students:
Hardin E, Adinoff B. Family history of alcoholism does not influence adrenocortical hyporesponsiveness in abstinent alcohol-dependent men. Am J Drug Alcohol Abuse. 34:151-160, 2008.
Poster presented at the 46th Annual Medical Student Research Forum
Rayhan Hai 5HT-3 Activity in Cocaine Addicts
Shivum Agarwal, Exploring Limbic-HPA System Function: Amygdalar and Hippocampal
Neural Activation Negatively Associated with Cortisol Response in Healthy Subjects
Poster presented at the 47th Annual Medical Student Research Forum