Response to corticotropin-releasing hormone infusion in cocaine-dependent individuals

Abstract

Context: Corticotropin-releasing hormone (CRH), through the hypothalamic pituitary adrenal axis and other brain stress systems, is involved in the emotional dysregulation associated with cocaine dependence. Little is known about the response of cocaine-dependent individuals to CRH administration.

Objective: The primary objective was to examine the hypothalamic-pituitary-adrenal axis and the subjective and physiologic response to CRH in cocaine-dependent individuals and controls.

Design: A case-control study.

Setting: Subjects were admitted to a General Clinical Research Center for testing and abstinence was verified with a urine drug screening.

Participants: Participants were male controls (n = 23), female controls (n = 24), cocaine-dependent men (n = 28), and cocaine-dependent women (n = 25). Individuals with dependence on other substances (except caffeine or nicotine) or with major depression, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded.

Intervention: Subjects received 1 microg/kg of CRH intravenously.

Main outcome measures: Primary outcomes included plasma corticotropin levels, cortisol levels, and heart rate and subjective measurements.

Results: Cocaine-dependent individuals exhibited higher stress (P < .001) and craving for CRH compared with controls. A positive correlation (r(s) = 0.51; P < .001) between stress and craving was found in cocaine-dependent subjects. Intravenous CRH elevated heart rates in all groups; however, cocaine-dependent women demonstrated a significantly higher heart rate at all time points (P = .05). Women had higher cortisol responses to CRH (P = .03). No effect of cocaine status was observed. The corticotropin response to CRH was independent of sex and cocaine dependence. Cortisol and corticotropin were positively correlated in the controls and cocaine-dependent men, but not in cocaine-dependent women (r(s) = 0.199; P = .4).

Conclusions: There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in hypothalamic pituitary adrenal axis response between the cocaine-dependent and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of nonhypothalamic stress-responsive CRH systems.

Figure 1

Subjective stress and craving in response to CRH. Stress (A) and craving (B) data are presented as group means (+se) from control males (closed triangles), control females (open triangles), cocaine dependent males (closed circles), and cocaine dependent females (open circles) during baseline (−20) and following CRH administration (time 0).

Figure 2

Positive correlation between peak stress and peak craving following CRH administration in cocaine dependent subjects. *Denotes Spearman’s rank correlation coefficient (r_s). P < 0.05 denotes a significance correlation between peak change in stress and peak change in craving.

Figure 3

Heart rate response to CRH. Mean heart rate response from control males (closed triangles), control females (open triangles), cocaine dependent males (closed circles), and cocaine dependent females (open circles) during baseline (−20 and −10) and following CRH administration Data are presented as group means +se (A). Responder analysis comparing peak change in heart rate between non-dependent controls (males and females) and cocaine dependent subjects (males and females) (B). Data are presented as group means +se, *Denotes a significant difference between the cocaine dependent and control groups.

Figure 4

Neuroendocrine response to CRH. Data are presented as group means (+se) from control males (closed triangles), control females (open triangles), cocaine dependent males (closed circles), and cocaine dependent females (open circles) during baseline (−20) and following CRH administration (time 0). Plasma ACTH was measured during baseline (−20) and at regular intervals following CRH infusion (time 0). (A) Plasma cortisol was measured during baseline (−20) and at regular intervals following CRH infusion (time 0). (B)

Figure 5

HPA dysregulation in cocaine dependent females. Correlation between peak change in plasma cortisol and peak change in plasma ACTH in response to CRH administration in control males (A) control females (B) cocaine dependent males (C) and cocaine dependent females (D). Data were analyzed using Spearman’s rank correlation coefficients (*r_s). P < 0.05 denotes a significance correlation between peak change in ACTH and peak change in cortisol.