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Cerebrospinal Fluid Corticotropin-Releasing Hormone in Healthy Humans: Effects of Yohimbine and Naloxone¹

Departments of Psychiatry (M.V., J.D.B., G.R.H., D.S.C.), Child Psychiatry (G.M.A.), and Anesthesiology (T.M.H.), Yale University School of Medicine, New Haven, Connecticut 06519; and Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine (M.J.O., C.B.N.), Atlanta, Georgia 30322

Address all correspondence and requests for reprints to: Meena Vythilingam, M.D., Mood and Anxiety Disorders Research Program, National Institute of Mental Health, 9000 Rockville Pike, Building 10, Room 4N222, Bethesda, Maryland 20892-1381. E-mail: Vythim{at}nih.gov

CRH neurons projecting from the paraventricular nucleus (PVN) of the hypothalamus to the median eminence control hypothalamic-pituitary-adrenal (HPA) axis activity. However, CRH neurons outside the PVN as well as PVN neurons projecting to sites other than the median eminence also contribute to the stress response and may play a role in mood and anxiety disorders. We have attempted to investigate possible noradrenergic and opioid regulation of these non-HPA CRH neurons. We hypothesized that yohimbine (an ₂-adrenergic antagonist) would have stimulatory action on non-HPA CRH neurons, whereas naloxone (a µ-opioid receptor antagonist) would not have this effect. Adult normal volunteers received iv yohimbine (n = 5; 0.4 µg/kg), naloxone (n = 4; 125 µg/kg), or placebo (n = 3; 0.9% saline). Cerebrospinal fluid (CSF) was collected continuously, and concentrations of CSF CRH, CSF norepinephrine (NE), and plasma cortisol were measured. Administration of either yohimbine or naloxone caused significant increases in plasma cortisol concentrations over time. Although yohimbine robustly increased CSF NE levels and appeared to increase CSF CRH levels, these effects were not seen after naloxone or placebo administration. Intraindividual correlations were not observed between the measured concentrations of plasma cortisol and CSF CRH for any of the subjects. The results support the idea that CSF CRH concentrations reflect the activity of non-HPA CRH neurons. Although both yohimbine and naloxone stimulated the HPA axis, only yohimbine appeared to have stimulatory effects on central NE and non-HPA CRH.

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