Stress, Hypothalamic-Pituitary-Adrenal (HPA) Dysfunction, and Relapse in Alcoholism

The hypothalamic-pituitary-adrenal (HPA) system is suggested as a key biologic link in
stress-induced relapse. 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
response to stress. The chronic use of alcohol may also impair the stress-induced release
of neurosteroids, compounds that directly modulate central nervous system activity. Thus,
altered cortisol and neurosteroid responsiveness during abstinence may impair the central
nervous system's ability to mount an appropriate response to environmental stressors,
heightening the probability of relapse. However, the relationship between stress, relapse,
and HPA axis disturbances remains tentative. In the proposed study, the investigators will
assess the contribution of trauma, stress, and alcohol use upon pituitary-adrenocortical
functioning in alcohol dependence. The relative contribution of adrenocortical disruption
and episodic stress to prospective drinking behaviors will then be determined.

Hypothesis: We hypothesize (1) that lifetime trauma, recent stress, and chronic alcohol use
will additively contribute to HPA axis disruption, (2) alterations in glucocorticoid and
neurosteroid release as well as episodic stress will predict a return to drinking.

Methods: One hundred treatment-seeking, one-month abstinent, alcohol-dependent subjects
will be studied. Standardized assessments will be used to assess childhood and adult trauma
as well as recent (six months) stress. Pituitary-adrenal (including ACTH, cortisol, and
neurosteroids) responses to both neuroendocrine [ovine corticotropin releasing hormone
(oCRH), cosyntropin, and dexamethasone] and experiential (public speaking) challenges will
be measured. Drinking behavior and episodic stress will be prospectively assessed for six
months following neuroendocrine assessment.

Significance: If our hypotheses are supported, a definitive connection between previous
trauma, biological stress response mechanisms, and ongoing stress upon prospective drinking
behavior will be demonstrated. The identification of a specific biologic mechanism that
underlies this association will provide a fertile framework for the development of targeted
pharmacological interventions to decrease relapse in this vulnerable population. In
addition, elucidating the concurrent contributions of stress-response biologic systems and
externals stressors will provide the therapist and patient with a constellation of specific
risk factors for focused treatment.

Inclusion Criteria:

- Diagnosis of alcohol dependence

Exclusion Criteria:

- Medical or psychiatric disorders that may effect stress-hormone axis functioning.

- Medications that may effect stress-hormone axis functioning.

- English speaking.