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Biomedical subjects

N H Kalin

Publications and source records attributed to N H Kalin.

At least 73 records · Page 4Linked to original sources

Effects of clonidine and propranolol on separation-induced distress in infant rhesus monkeys.

In primates, separation of an infant from its mother is a naturally occurring stressor resulting in activation of behavioral, endocrine, and autonomic systems. When separated from their mothers, infant rhesus monkeys emit frequent species-typical distress vocalizations ('coos'). In earlier work we demonstrated that opiate and benzodiazepine systems influence the frequency of coos induced by separation in infant rhesus monkeys. The present studies assessed the role of alpha 2- and beta-adrenergic systems in mediating distress vocalizations. We found that the alpha 2 agonist, clonidine (33 and 67 micrograms/kg), reduced activity levels without affecting separation-induced coos. Only at 100 micrograms/kg were distress vocalizations reduced, and this was associated with behavioral sedation. In the same animals, morphine (0.1 and 0.25 mg/kg) selectively reduced distress vocalizations without affecting activity. Thus, the effects of clonidine, 100 micrograms/kg, appear to be due to non-specific sedation. We next assessed whether antagonism of beta-adrenergic receptors reduces separation distress. We administered propranolol over a wide dosage range to a different group of animals and found that a high dose (20 mg/kg) increased separation-induced coos while decreasing the activity levels. That such a high dose was necessary to affect coo vocalizations suggests that effects on vocalizations are due to non-specific effects of the drug. Unlike propranolol, morphine administered to these animals did not affect activity levels but did selectively reduce distress vocalizations. These findings suggest that alpha 2- and beta-adrenergic systems do not specifically mediate separation-induced coos in infant rhesus monkeys. However, as demonstrated in an earlier study, opiate systems have a prominent role.

Animals↗

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.

Animals↗

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)

Adrenocorticotropic Hormone↗

ICV-CRH alters stress-induced freezing behavior without affecting pain sensitivity.

Freezing is an adaptive response often induced by stressful, fear-eliciting stimuli. Three experiments with rats investigated the effects of intracerebroventricular (ICV) administration of corticotropin-releasing hormone (CRH) on freezing behavior and pain sensitivity. Experiments 1 and 3 demonstrated that ICV-CRH (300 ng) enhanced shock-elicited freezing. In Experiment 1, ICV-CRH also enhanced recovery from shock-elicited freezing, suggesting that the peptide has a biphasic effect. Experiments 2 and 3 established that CRH-induced freezing was not caused by heightened pain sensitivity. Interestingly, in Experiment 2, hot-plate exposure produced increased freezing that was attenuated by ICV-CRH. Thus, the direction of the ICV-CRH effect on freezing was found to depend on the nature of the stressor. These results suggest that endogenous CRH systems modulate stress-induced freezing.

Animals↗

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.

Adrenal Glands↗

Separation distress in infant rhesus monkeys: effects of diazepam and Ro 15-1788.

Disruption of the primate mother-infant attachment bond is a naturally occurring stressor that results in marked behavioral, physiological, and endocrine activation. We studied the effect that altering benzodiazepine systems has on the behavioral and endocrine response of infant rhesus monkeys (1-27 weeks of age) to brief separation from their mothers. In the first experiment, the benzodiazepine agonist diazepam (0.1 and 1.0 mg/kg) significantly increased locomotion and social behavior and decreased inactivity and distress vocalizations in infant monkeys undergoing separation. In the second experiment, the benzodiazepine antagonist Ro 15-1788 (5 and 10 mg/kg) had no significant effects on the infants' separation response. In the third experiment, administration of diazepam 1.0 mg/kg was followed by administration of Ro 15-1788 10 mg/kg in infants undergoing separation. Ro 15-1788 blocked the decreases both in inactivity and in plasma ACTH and cortisol concentrations caused by diazepam, suggesting that these effects are mediated through benzodiazepine receptors. These data support the hypothesis that in primates, endogenous benzodiazepine systems modulate the behavioral and endocrine response to the naturally occurring stress of separation.

Adrenocorticotropic Hormone↗

The effects of ICV-CRH on novelty-induced behavior.

To assess whether centrally administered corticotropin-releasing hormone (CRH) modulates behavioral and antinociceptive effects of exposure to a novel environment, vehicle or 0.03, 0.3, or 3.0 micrograms of CRH was administered intracerebroventricularly (ICV) to rats, which were then tested under novel or familiar conditions. Novelty decreased sleeping and grooming and increased rearing, walking, and latency to respond on the hot-plate test of analgesia. CRH increased grooming and walking, decreased rearing and sleeping, and had no effect in the hot-plate test. The lowest dose was without effect on any measure; otherwise, CRH effects generally were dose-dependent. There was no evidence that CRH selectively enhanced or interfered with novelty-induced behavioral changes; it influenced behavior to the same degree in both test conditions. However, test condition selectively modulated the degree of peptide-induced self-gnawing and burrowing.

Animals↗

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.

Adrenal Cortex↗

Rise in plasma beta-endorphin, ACTH, and cortisol in cancer patients undergoing whole body hyperthermia.

It has been previously reported that sauna-induced fevers (approximately 39 degrees C) result in rises of beta-endorphins in normal volunteers. This report describes changes in plasma beta-endorphins in cancer patients undergoing whole body hyperthermia (40.5 degrees C to 41.8 degrees C). Results presented show that there is a linear relationship between thermal stress, defined in terms of core temperature and/or duration of hyperthermia, and the quantitative rise in plasma beta-endorphin levels. Data relating to changes in ACTH and cortisol levels are in a single temperature range (41.5 degrees C--41.8 degrees C) are also reported.

Adolescent↗

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.

Adrenocorticotropic Hormone↗

ICV-CRH potently affects behavior without altering antinociceptive responding.

To explore the hypothesized integrative function of corticotropin releasing hormone (CRH) in the stress response, stress-related behaviors including antinociception were studied in rats after either intracerebroventricular (ICV) or peripheral administration of CRH. The effects of low-dose (0.3 microgram) and high-dose (3.0 micrograms) ICV-CRH were compared to those of vehicle, employing a within-S design. The two doses yielded comparable behavioral changes suggestive of increased arousal and stress. These changes were characterized by significant increases in grooming, walking, burrowing, self-gnawing, and pica, and decreases in rearing and sleeping. None of these effects of ICV-CRH were obtained with peripheral administration of the same doses. The hot-plate test of analgesia failed to show a significant effect of ICV-CRH or peripherally administered CRH. A between-S experiment incorporating both the tail-flick and the hot-plate tests of analgesia compared ICV-CRH (3.0 micrograms) with vehicle. ICV-CRH did not affect antinociceptive responding in either of these tests. In contrast, ICV morphine (10 micrograms) yielded potent analgesia in both tests. Thus, with doses of ICV-CRH yielding clear evidence of stress-related behavior, no evidence of analgesia was obtained. These findings question the possible role of central CRH systems in antinociceptive processes.

Analgesia↗

ACTH in plasma and CSF in the rhesus monkey.

Adrenocorticotrophic hormone (ACTH) and other biosynthetically related peptides are found both in the brain and peripherally, but the function and regulation of these substances differ in the brain and in the periphery. It has been suggested that measurement of peptide hormones in the cerebrospinal fluid (CSF) might provide information relevant to the diagnosis and pathophysiology of neurological and psychiatric illnesses. We report experiments using a rhesus monkey model to evaluate parameters affecting CSF ACTH concentrations. We found that CSF ACTH concentrations follow a diurnal rhythm that is markedly different from that in plasma, concentrations of ACTH in monkey CSF, but not in plasma, increased significantly after 4 days of social separation, and CSF ACTH concentrations did not change after hypophysectomy. These results suggest that CSF ACTH concentrations reflect the activity of brain and not peripheral ACTH systems.

Adrenocorticotropic Hormone↗

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.

Adrenocorticotropic Hormone↗

A rostral-caudal concentration gradient in cerebrospinal fluid adrenocorticotropin.

In two separate experiments, cerebrospinal fluid (CSF) adrenocorticotropin immunoreactive (ACTH-IR) concentrations in the rhesus monkey followed a significant rostral-caudal gradient. In the first study, CSF was sampled from an indwelling catheter in awake animals. The mean ACTH-IR concentration in the cisternal region was 12.3 pg/ml, as compared to 8.56 pg/ml in the lumbar region. In the second study, CSF was sampled in a different group of monkeys by percutaneous puncture at the cisterna magna and at L5-L6. In this study, the mean ACTH-IR concentration in samples collected from the cistern was also greater than the concentration from L5-L6. In addition, a significant correlation within subjects was found between samples collected from the two sites (r = 0.86). These results demonstrate that the site of CSF sampling is a variable in determining CSF ACTH-IR concentrations and suggest that lumbar CSF ACTH-IR concentrations in humans may be interpreted as indexes of ACTH changes at higher levels in the central nervous system.

Adrenocorticotropic Hormone↗

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.

Adrenocorticotropic Hormone↗

The diurnal variation of immunoreactive adrenocorticotropin in rhesus monkey plasma and cerebrospinal fluid.

ACTH immunoreactivity (ACTH-IR) in the plasma and cerebrospinal fluid (CSF) collected simultaneously from rhesus monkeys was found to undergo significant diurnal variations. In plasma, the mean peak ACTH-IR was 15.4 +/- 1.95 pg/ml at 0500 h, and the mean minimum concentration was 9.05 +/- 1.80 pg/ml at 1800 h. In CSF, the mean peak ACTH-IR concentration occurred at 1900 h and was 4.64 +/- 0.41 pg/ml. The mean minimum CSF ACTH-IR concentration was 2.93 +/- 0.26 pg/ml, occurring at 0500 h. This is the first report of a diurnal variation in CSF ACTH-IR concentration and is consistent with other work suggesting that plasma ACTH and CSF ACTH originate from different sources.

Adrenocorticotropic Hormone↗

Depression in bulimia at 2- to 5-year followup.

Previous research has indicated a strong association between bulimia and affective disorder at the time of initial clinical assessment. To investigate this relationship from a long-term perspective, 30 normal weight female bulimics were evaluated 2 to 5 years posthospital admission with psychometric measures and clinical interviews. Contrary to previous reports, the depression scores of the bulimics were surprisingly low, even though 26 of the 30 continued to fulfill DSM-III criteria for bulimia. Higher depression scores were associated with more intense bulimic symptomatology and attitudes, and greater psychiatric disturbance at followup. Although these data demonstrate a relationship between bulimic symptomatology and depression at long-term followup, they do not support recent assertions that bulimia is a variant of an underlying affective disorder.

Adolescent↗