Elevated CSF Corticotropin-Releasing Factor Concentrations in Posttraumatic Stress Disorder

Corticotropin-releasing factor (CRF) plays an important role in mediating the mammalian stress response (1). CRF released during stress (2) from nerve terminals originating in the paraventricular nucleus of the hypothalamus increases the secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary, which in turn stimulates release of cortisol from the adrenal (3). Cortisol has a number of effects that are beneficial to short-term survival, including suppression of reproductive and immune function, promotion of analgesia, activation of the peripheral autonomic system, suppression of gastric motility and gastric acid secretion, and increases in total oxygen consumption and glucose and glucagon concentrations in plasma (3). Chronic stress results in sustained increases in plasma glucocorticoid levels (4), with a potentiation of glucocorticoid responsiveness to subsequent stressors (5, 6) and neuronal “hypersecretion” of CRF. CRF neurons are distributed in a variety of locations outside of the hypothalamus, including the amygdala, bed nucleus of the stria terminalis, central gray area, locus ceruleus, parabrachial area, and dorsal vagus complex (7). Intraventricular administration of CRF to laboratory animals results in behavioral activation, as evidenced by 1) an increase in EEG activity (8); 2) increases in plasma norepinephrine and epinephrine concentrations (9, 10); 3) an increase in firing of the locus ceruleus, site of the majority of noradrenergic cell bodies in the brain, which results in a state of increased attention and arousal (11); 4) increased locomotor activity, grooming, and rearing (12); and 5) behaviors consistent with anxiety and fear, including a decrease in exploratory activity in an open field (13), decreased punished responding in the conflict test (14), and potentiation of acoustic startle (15, 16). These studies support an important role for CRF in the promotion of anxiety and fear-related behaviors. Findings from clinical studies are consistent with a relationship among CRF, stress, and depression (which has been conceptualized as a chronic stress disorder). Studies in patients with depression consistently reveal an increase in CSF concentrations of CRF and a blunted ACTH response to intravenously administered CRF (17–19). Patients with posttraumatic stress disorder (PTSD) have been found to exhibit alterations in hypothalamic-pituitary-adrenal (HPA) axis function (20, 21), although no studies have directly measured CRF in the CSF in patients with PTSD. Somatostatin is a tetradecapeptide with widespread localization in the CNS that also appears to play a role in the stress response (22–24). Somatostatin and CRF levels tend to covary with one another, so it would be predicted that increased levels of CRF would be associated with increased levels of somatostatin. CSF somatostatin concentrations in patients with affective disorders, however, have been found to be either lower than (25–27) or the same as (28) those of comparison subjects (although elevated levels of somatostatin are seen in mania [29]). The purpose of the present study was to measure CSF CRF and somatostatin concentrations in Vietnam combat veterans with PTSD and matched comparison subjects. We hypothesized that PTSD would be associated with elevated CSF levels of CRF and somatostatin.