Charles M. Barksdale

Opiate modulation of separation-induced distress in non-human primates.

Infant rhesus monkeys respond to separation from their mothers with a dramatic increase in vocalizations and activation of autonomic and pituitary-adrenal systems. Using the mother-infant separation paradigm in rhesus monkeys, we focused on the role of opiate systems in modulating the behavioral and neuroendocrine consequences of a brief, naturally occurring stressor. In the first experiment, morphine 0.1 mg/kg significantly decreased separation-induced vocalizations without affecting activity levels. In the second experiment, naloxone 1.0 mg/kg increased distress vocalizations but lower doses had no effect. In the third experiment we blocked the effect of morphine 0.1 mg/kg with naloxone 0.1 mg/kg, a dose of naloxone that had no intrinsic effects of its own. This suggests that the reduction of separation-induced vocalizations by morphine is mediated by opiate receptors. The last experiment demonstrated that separation-induced increases in pituitary-adrenal hormones can also be modulated by opiate agonists and antagonists. These findings are consistent with work in non-primate species and support the hypothesis that opiate receptors are specifically involved in mediating separation-induced vocalizations and pituitary-adrenal activation in primates.

Mood state and salivary cortisol levels following overtraining in female swimmers

Mood, as measured by the Profile of Mood States questionnaire, and resting salivary cortisol levels were examined in 14 female college swimmers during progressive increases and decreases in training volume, and were compared to the same measures in eight active college women who served as controls. Training volume increased from 2,000 yards/day in September (baseline) to a peak of 12,000 yards/day in January (overtraining), followed by a reduction in training (taper) to 4,500 yards/day by February. The swimmers experienced significant (p less than 0.01) alterations in tension, depression, anger, vigor, fatigue and global mood across the training season compared to the controls. Salivary cortisol was significantly (p less than 0.01) greater in the swimmers compared to the controls during baseline and overtraining, but was not different between the groups following the taper. Salivary cortisol was significantly correlated with depressed mood during overtraining (r = .50; p less than 0.05) but not at baseline or taper. Global mood, depression, and salivary cortisol were significantly (p less than 0.05) higher during the overtraining phase in those swimmers classified as stale, compared to those swimmers who did not exhibit large performance decrements.

Stressor controllability and the pituitary-adrenal system

Stressor controllability can alter both behavior and pituitary-adrenal activity. Potential mediation of these behavioral effects by differential pituitary-adrenal output requires that the precise conditions that lead to differential behavioral consequences also produce differential pituitary-adrenal activity. Both plasma ACTH and corticosterone levels were measured at various times following escapable and yoked inescapable electric shock conditions known to produce differential behavioral outcomes. The escapable and inescapable shock procedures did not produce a detectable differential effect. Both shock conditions produced equivalent elevation of ACTH and corticosterone. Neither decay rates nor the ACTH and corticosterone response to shock reexposure differed among shocked groups.

Stressor controllability during pregnancy influences pituitary-adrenal hormone concentrations and analgesic responsiveness in offspring

Repeated escapable shock, yoked-inescapable shock, or no-shock treatments were administered to female rats before parturition to investigate the effects of stressor controllability on offspring pituitary-adrenal hormone concentrations and stress-induced analgesic reactions. Female rats exposed to escapable shock treatments received tail-shock in boxes containing a wheel that allowed shocks to be terminated after rotation. Rats in the yoked-inescapable shock group received an identical amount and pattern of tail-shock. However, shock was terminated only after wheel rotation by the rat undergoing escapable shock treatments. Female rats in the no-shock group were simply placed in wheel-turn boxes. Fourteen-day-old offspring were exposed for 10-min to either a separation-stress or shock-induced stress test. The former test consisted of separating and isolating the pup from the mother and siblings, whereas the latter involved the administration of five brief, 1.0 sec, low intensity, 0.5 mA, foot-shocks. Immediately after exposure to foot-shocks, pups were given a tail-flick test to assess their analgesic response. Plasma was obtained from pups immediately after separation and tail-flick tests and ACTH and corticosterone concentrations were assayed by radioimmunoassay. Results indicated that prenatal inescapable shock treatments resulted in offspring with significantly higher plasma ACTH and corticosterone concentrations than offspring exposed to prenatal escapable shock or no-shock treatments. Offspring of females exposed to inescapable shock also exhibited greater increases from basal concentrations in ACTH and corticosterone after stress. Furthermore, prenatal escapable and inescapable shock treatments significantly altered shock-induced analgesic thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)

A diurnal rhythm in cerebrospinal fluid corticotrophin-releasing hormone different from the rhythm of pituitary-adrenal activity

Corticotrophin-releasing hormone (CRH) appears to be involved in the pathophysiology of various neuropsychiatric illnesses. Because of the potential importance of determining CRH concentrations in cerebrospinal fluid (CSF) in humans and the constraints on human experimentation, we used a rhesus monkey model to study factors affecting CSF-CRH concentrations and the association between CRH concentrations and changes in plasma ACTH and cortisol levels. CSF-CRH concentrations followed a diurnal rhythm not closely linked to that of the anterior pituitary-adrenal system. Manipulations that increased release of pituitary ACTH did not affect CSF-CRH concentrations. Our data show that sampling time should be controlled in human CSF-CRH studies and suggest that altered CSF-CRH levels reflect dysregulation of extrahypothalamic CRH neurons.

Effects of Dexamethasone on Central and Peripheral ACTH Systems in the Rat

To investigate the simultaneous effects of dexamethasone on peripheral and central adrenocorticotropic hormone (ACTH) systems, rats were treated with dexamethasone or saline for 4 days. Pituitary, plasma, hypothalamus and cerebrospinal fluid (CSF) were then collected and analyzed for ACTH immunoreactivity. Additionally, hypothalamic tissue extracts were analyzed for corticotropin-releasing hormone (CRH) immunoreactivity. Dexamethasone significantly lowered peripheral levels of ACTH as measured in pituitary and plasma. Hypothalamic ACTH content significantly increased while CSF ACTH significantly decreased with dexamethasone treatment. Hypothalamic CRH concentrations showed a small but statistically insignificant decrease. These results suggest that prolonged exposure to dexamethasone affects central as well as peripheral ACTH activity, corroborate our previous findings in rhesus monkeys of decreased CSF ACTH in response to prolonged dexamethasone treatment, suggest that dexamethasone may inhibit the release of ACTH from hypothalamic neurons into the CSF, and provide evidence that the effect of dexamethasone on pituitary ACTH content is of greater magnitude than its effect on hypothalamic CRH.

Behavioral stress decreases plasma oxytocin concentrations in primates

Using rhesus monkeys, we studied the effects of a behavioral stress on plasma concentrations of adrenocorticotropin, oxytocin, and vasopressin. The stress resulted in significant increases in adrenocorticotropin and significant decreases in oxytocin concentrations. No significant changes were seen in vasopressin concentrations. To further explore the relationship between plasma oxytocin and pituitary-adrenal function, dexamethasone was administered to rhesus monkeys. This resulted in significant increases in plasma oxytocin concentrations, while adrenocorticotropin decreased.

Function of the adrenal cortex in patients with major depression

Failure to suppress cortisol secretion after administration of dexamethasone occurs in up to 50% of depressed patients. To test whether this hypothalamic-pituitary-adrenal (HPA) overactivity is associated with adrenocortical hyperresponsiveness, we performed dexamethasone suppression tests (DSTs) and adrenocorticotropic hormone (ACTH) stimulation tests in depressed subjects and subjects with other psychiatric disorders. Three groups were defined: depressed nonsuppressors, depressed suppressors, and other suppressors. While predexamethasone and postdexamethasone cortisol concentrations were greater in the depressed nonsuppressor group, ACTH concentrations did not differ among groups. After receiving alpha-ACTH[1-24] (4.2 micrograms/kg), depressed nonsuppressors had greater increases in stimulated cortisol secretion than the other groups. These results demonstrate that in a subgroup of depressed patients, HPA overactivity is associated with adrenocortical hyperresponsiveness.

Effects of Acute Behavioral Stress on Plasma and Cerebrospinal Fluid ACTH and β-Endorphin in Rhesus Monkeys

To elucidate the effect of acute behavioral stress on plasma and cerebrospinal fluid (CSF) concentrations of adrenocorticotropic hormone (ACTH) and beta-endorphin, rhesus monkeys were subjected to 30 min of confinement stress. Simultaneous plasma and CSF samples revealed no significant change in CSF ACTH or beta-endorphin up to 120 min after the onset of the stress despite significant elevations in plasma cortisol, ACTH, and beta-endorphin. It is suggested that acute behavioral stress does not alter CSF ACTH or beta-endorphin, and that this information may be clinically useful for future human studies of CSF ACTH and beta-endorphin in neuropsychiatric illnesses.

Immunoneutralization of corticotropin-releasing hormone prevents the diurnal surge of acth

To determine whether CRH is required for the evening rise in plasma ACTH, rats were injected at 0800 hr with CRH antiserum (anti-CRH) or normal rabbit serum (NRS). Blood samples were taken through venous catheters at 0800 hr before treatment and at 1300, 1700, and 2100 hr. Plasma was assayed for immunoreactive ACTH and corticosterone. There was no significant difference in pretreatment values between the two groups. Immunoneutralization of CRH abolished the rise in plasma ACTH seen at 1700 hr in the NRS group but had little effect on earlier levels. The diurnal elevation in plasma corticosterone continued after anti-CRH treatment, but peak levels occurred earlier. Plasma ACTH and corticosterone were significantly correlated at the time of the diurnal surge, but not at 0800 hr or 1300 hr in the NRS controls or at any time point in the anti-CRH group. These results suggest that CRH is required for the diurnal surge of plasma ACTH. They also confirm previous observations by others that the adrenal cortex does not require active CRH or a diurnal surge of ACTH in order to exhibit a significant diurnal increase in secretion of corticosterone, and that factors other than CRH may be relatively more active than CRH in regulation of ACTH secretion during the time of circadian inactivity.