Edward Geller

Neonatal Adrenal Cortical Response to Stress and Vasopressin.

Summary The adrenal cortical response to electric shock stress was studied in rats of various ages. Measurements of both adrenal corticosterone and ascorbic acid changes in the same gland indicated that no response occurred until the animals were approximately 8 days old, at which time stress caused changes in both these substances. The early postnatal period in the ratslife when stress does not result in pituitary-adrenal activation we propose to call the stress-non-responsive period (S-N-R period). Both synthetic and commercial vasopressin administered to rats during the S-N-R period caused an increase in corticosterone content of the adrenal gland, and less consistently a decrease in ascorbic acid. It is suggested that the S-N-R period may be related to immaturity of the hypothalamic osmoreceptor mechanism which underlies adjustments in vasopressin secretion.

EFFECTS OF ENVIRONMENTAL COMPLEXITY ON CONSTITUENTS OF BRAIN AND LIVER

IN a series of studies KRECH, ROSENZWEIG, BENNETT (1960, 1962) and co-workers (ZOLMAN and MORIMOTO, 1962; ROSENZWEIG, KRECH, BENNETT and ZOLMAN, 1962; ROSENZWEIG, BENNETT and KRECH, 1964; BENNETT, KRECH and ROSENZWEIG, 1964~) demonstrated that rats maintained under conditions of ‘environmental complexity and training’ (ECT) had significantly higher btain cortex weights than isolated controls (IC). Further, they showed that ECT animals differed from IC animals in activity and distribution in the brain of acetylcholinesterase but not of total protein, hexokinase, or serotonin (BENNETT, DIAMOND, KRECH and ROSENZWEIG, 1964b). It appeared to us that these environmental conditions, being sufficiently profound to alter weights of portions of the brain, might reasonably be expected also to influence parameters of brain function. Such responses to early environment may be regarded as internalization of external stimuli (learning?, memory?) and for this reason it seemed particularly important to investigate those aromatic amines that have been associated with neurohumoral transmission and which may reflect such an internalization. In addition, it appeared reasonable to us that these environmental conditions may be stressful, and that a consequent chronic activation of the pituitary-adrenal system may occur. A series of enzymes may thereby be stimulated or inhibited leading to more widespread changes. Although BENNETT et al. (19646) reported no change in adrenal weights under IC conditions, we felt that the possibility of isolation stress should be pursued further by measuring adrenal and plasma corticoid levels and the activities of several enzymes known to be responsive to high circulatory levels of corticoid.

Effects of L-dopa in autism

A study was designed to determine if blood serotonin concentrations could be lowered in autistic children by the administration of L-dopa and, if so, to observe possible clinical or physiological changes. Following a 17-day placebo period, four hospitalized autistic boys (3, 4, 9, and 13 years of age) received L-dopa for 6 months. Results indicated a significant decrease of blood serotonin concentrations in the three youngest patients, a significant increase in platelet counts in the youngest patient, and a similar trend in others. Urinary excretion of 5HIAA decreased significantly in the 4-year-old patient and a similar trend was noted in others. No changes were observed in the clinical course of the disorder, the amount of motility disturbances (hand-flapping), percent of REM sleep time, or in measures of endocrine function (FSH and LH). Possible mechanisms by which L-dopa lowered blood serotonin concentrations, increased platelet counts, and yet failed to produce other changes are discussed.

Effects of chronic fenfluramine on blood serotonin cerebrospinal fluid metabolites and behavior in monkeys

The effects of long term (70 days) fenfluramine treatment on selected physiological and behavioral measures were examined in four adult male vervet monkeys (Cercopithecus aethiops sabaeus). Relative to pretreatment baseline values, whole blood serotonin (WBS) and cerebrospinal fluid 5-hydroxyindole acetic acid (5-HIAA) were reduced, cerebrospinal fluid homovanillic acid (HVA) was unaltered, and aggressive and locomotor behavior were increased. Both physiological and behavioral effects were reversible: all measures returned to baseline values in the 35 day post-treatment period, with WBS resuming pretreatment values more rapidly than CSF 5-HIAA. At the relatively low doses (1–4 mg/kg/day) employed in the present study fenfluramine produced behavioral effects similar to those resulting from PCPA and opposite to those following tryptophan administration. Thus the behavioral effects of long-term fenfluramine may involve reductions in serotonergic transmission.

Harderian Gland: Development and Influence of Early Hormonal Treatment on Porphyrin Content

The porphyrin content of the rat Harderian gland remains low until 12 days of age at which time both porphyrin content and concentration rapidly increase. Intraperitoneal administration of tetraiodothyronine (thyroxine) into newborn animals advances the appearance of porphyrin in the gland. Conversely, a single injection of cortisol acetate into newborns retards the appearance of porphyrin. The time of porphyrin appearance in the gland parallels the time for maturation of the evoked cortical response to visual stimulation in normal and hormone-treated animals.

Fenfluramine effects on serotonergic measures in vervet monkeys.

Chronic fenfluramine treatment reduced whole blood serotonin and CSF 5-hydroxyindoleacetic acid, but increased aggressive and locomotor behavior, in adult male vervet monkeys (Cercopithecus aethiops sabaeus). Following a drug-free washout period to monitor the drug recovery course, we initiated a second period of fenfluramine treatment in the same animals. When whole blood serotonin concentrations were reduced by about 40% from predrug baseline levels, we examined 11 cortical and subcortical brain regions for their content of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, norepinephrine, and dopamine. We observed correspondence between the reduction in whole blood serotonin and the reduction in brain 5-hydroxytryptamine. Similarly, there was a correspondence between the reduced 5-hydroxyindoleacetic acid levels observed in CSF and brain. No alterations were noted in the concentrations of norepinephrine or dopamine. These observations suggest that the behavioral effects observed in monkeys after chronic fenfluramine treatment result from reduced central serotonin.

Harderian Gland: Influence on Pineal Hydroxyindole-O-Methyltransferase Activity in Neonatal Rats

A circadian rhythm has been found in hydroxyindole-O-methyltransferase activity of the pineal gland of blinded 12-day-old rats. Five additional hours of lighting can partly prevent the nocturnal increase in pineal hydroxyindole-O-methyltransferase activity in such rats. Removal of the Harderian gland abolishes this response to light in 12-day-old blinded animals, giving further support to the suggestion that this gland may function as an extraretinal photosensitive organ influencing the pineal gland in blinded suckling rats.

Alterations in induction of tyrosine aminotransferase and tryptophan oxygenase by glucose pretreatment

Abstract 1. 1. This study was designed to examine the influence of glucose consumption on induction of tyrosine aminotransferase (EC 2.6.1.5) and tryptophan oxygenase (EC 1.11.1.4) by glucocorticoids, trytophan and casein. 2. 2. Glucose feeding lowers basals levels of these enzymes and the magnitude of the rise in levels after inducer. The ratio between induced and basal enzymes and the magnitude was essentially unaffected. Glucose treatment did not simply delay induction of these enzymes by inducer but rather depressed enzyme levels throughout the period of enzyme induction. 3. 3. In adrenalectomized animals, glucose pretreatment lower the induction of these enzymes by casein but not by tryptopha. 4. 4. These and other observations lead us to suggest that tryptophan oxygenase functions to regulate intracellular tryptophan levels and that tryptophan levels play a key role in shifting metabolism between protein synthesis and gluconeogenesis.

Platelet size, number, and serotonin content in blood of autistic, childhood schizophrenic, and normal children.

Platelet volumes were measured in 19 autistic, 26 normal, and 6 schizophrenic children with similar blood serotonin concentrations. The groups did not significantly differ in platelet volumes, nor did platelet volumes and blood serotonin concentrations correlate. These results do not support the hypothesis that the hyperserotoninemia in some autistics reflects increased platelet volume.

Effects of Neonatal Hydrocortisone Treatment on Pituitary and Adrenocortical Response to Stress in Young Rats

Administration of corticosteroids to rat pups within the first several days of life results in retardation of several behavioral, neurophysiological, and biochemical developmental patterns. At 25 days of age, animals treated neonatally with 1.0, 0.5, or 0.1 mg hydrocortisone acetate showed dose-dependent decreases in plasma ACTH following 2.5 min continuous exposure to ether. On day 20, plasma corticosterone values did not differ between these groups 15 min after ether stress, but lower values were seen 60 min after ether in animals treated at birth with 0.5 mg hydrocortisone. At 45--48 days of age, hydrocortisone-treated animals exposed to one of 2 different stressors showed decreased plasma corticosterone response to stress; females had lower corticosterone levels following both stressors, while males showed suppressed corticosterone levels following exposure to the mild (novelty) but not to the intense (ether) stress. These data demonstrate that neonatal exposure to hydrocortisone results in decreased CNS-pituitary responsivity to stress at 20--25 days of age, and that the adrenocortical response to stress in impaired at 45--48 days of age.