Biomedical subjects

S M Schanberg

Publications and source records attributed to S M Schanberg.

At least 19 recordsLinked to original sources

PubMed1999

Involvement of c-myc and max in CNS beta-endorphin modulation of hepatic ornithine decarboxylase responsiveness to insulin in rat pups.

Previously, we have shown that subcutaneous administration of insulin stimulates ornithine decarboxylase (ODC) mRNA expression and enzymatic activity in the liver of infant control rats, but not in those pretreated intracerebroventricularly (i.c.v.) with beta-endorphin. This finding is consistent with the hypothesis that beta-endorphin synthesized in the brain plays a prime role in the control of postnatal development, in part, by modulating ODC gene transcription. We now report that insulin induced stimulation of hepatic ODC mRNA expression is accompanied by a concomitant increase in the expression of c-myc and max mRNAs, and that this effect is also inhibited by pretreatment with i.c.v. beta-endorphin. These results suggest that CNS beta-endorphin suppresses tissue ODC responsiveness to trophic hormones by downregulating the expression of c-myc and max mRNAs, the encoded proteins of which are known to act physiologically as transcriptional activators of the ODC gene.

Animals↗

PubMed1999

Glucocorticoid regulation of ornithine decarboxylase in the postnatal rat lung.

Ornithine decarboxylase (ODC) is thought to play a critical role in pulmonary development. The purpose of this study was to characterize the effects of dexamethasone on ODC gene expression and enzyme activity in the lung of rat pups. Subcutaneous administration of dexamethasone (10 mg/kg) was shown to suppress ODC activity in 2-, 6- and 10-day-old rats for as long as 24 h after injection. In contrast, dexamethasone treatment stimulated liver ODC activity indicating that the inhibition of lung ODC is tissue specific. Contrary to expectation, the glucocorticoid enhanced lung ODC expression as indicated by an increased accumulation of ODC mRNA transcripts. The latter effect was associated with an heightened expression of c-myc and max mRNAs, the encoded proteins of which act as transactivators of the ODC gene. Dexamethasone did not alter lung levels of"antizyme" (AZ), an inducible protein that specifically promotes the degradation of the ODC protein enzyme. However, the lack of AZ induction does not necessarily mean that ODC degradation is not the mechanism for the decrease in lung ODC activity of dexamethasone-treated animals. The results obtained indicate that glucocorticoids can downregulate lung ODC activity, and that the effect is mediated by post-transcriptional rather than transcriptional mechanisms. These findings are consistent with the idea that endogenous glucocorticoids play an important role in the modulation of ODC activity and early pulmonary development.

Animals↗

PubMed1997

The influence of dietary cholesterol on cardiac and hepatic Beta-adrenergic receptors in egyptian sand rats.

We examined the effects of dietary cholesterol on cardiac and hepatic beta-adrenergic receptor functioning. Age-matched adult desert rodents (Psammomys obesus) were randomized to either a 5% cholesterol diet (CD, n = 20), or normal rabbit chow (RC, n = 18). After a 2-month exposure to the diets, animals were sacrificed and tissue from both heart and liver were retained for radioligand bindings studies. In heart tissue, cholesterol fed animals, relative to controls, showed an increased production of adenosine 3,5>-cyclic monophosphate (cAMP) in response to isoproterenol. Cholesterol supplementation was not associated with an increase in heart beta-adrenergic receptor number. Animals fed the 5% cholesterol diet showed significant increases in the number of beta-adrenergic receptor sites in hepatic tissue (M = 13.2 vs. 10.4 pmol/mg protein, CD and RC, respectively). The increased number of receptor sites in the liver was accompanied by a significant increase in isoproterenol-stimulated cAMP production. Results are supportive of the hypothesis that dietary cholesterol contributes to an upregulation of beta-adrenergic receptor function in cardiac, as well as hepatic tissue. These findings may be relevant to the observations of excessive stress-induced cardiovascular reactivity in persons with high cholesterol levels.

Journal Article↗

PubMed1997

Differential responsivity of monocyte cytokine and adhesion proteins in high- and low-hostile humans.

This study tested the general hypothesis that high- and low-hostile respondents would show different patterns of change in monocyte cytokine and adhesion protein (MCAP) expression in response to pharmacologically induced alterations in sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) balance. On 3 separate days, 4 high- and 4 low-hostile respondents received isoproterenol infusions after saline, atropine (PNS blockade), or neostigmine (PNS stimulation) pre-treatment. Dual color flow cytometry with fluorescently labeled monoclonal antibodies to CD 14 (monocyte market), interleukin-1, leukocyte function activator (LFA-1), Class II major histocompatibility complex (MHC-II), and tumor necrosis factor was used to quantify cytokine and adhesion protein expression on monocytes in blood samples drawn before and after the combination drug infusions on the 3 test days in each respondents. Following PNS stimulation and istoproterenol infusion there was a decrease (compared to saline pretreatment) in MHC II expression in high hostiles that was significantly (p<.02) different from an increase in low hostiles. A similar trend (p = .08) was seen for LFA-1 expression, with high hostiles showing an increase and low hostiles a decrease. These findings support the broad hypothesis that high-and low-hostile respondents will show different MCAP responses to pharmacologically induced alterations in SNS-PNS balance. Such differences could contribute to accelerated atherogenesis among high-hostile individuals.

Journal Article↗

PubMed1996

Neonatal deprivation of maternal touch may suppress ornithine decarboxylase via downregulation of the proto-oncogenes c-myc and max.

Previously, we have shown that short-term (1 hr) separation of neonatal rats from their mother (MS) suppresses basal ornithine decarboxylase (ODC) synthesis and tissue ODC response to trophic factors. This effect in the pup is caused by absence of maternal tactile stimulation (touch) but not from lack of maternal nutrients (food). This study was performed to examine in 10-d-old rats whether maternal touch deprivation affects expression of certain hepatic proto-oncogenes, the protein products of which are known to interact with the regulatory region of the ODC gene. Prolactin (PRL) injected subcutaneously increased hepatic ODC activity as well as mRNA levels of ODC and the proto-oncogenes c-fos, c-jun, junB, junD, c-myc, and max. MS significantly suppressed PRL-induced increases in ODC enzyme activity and c-myc, max, and ODC mRNAs but had little effect on expression of the other proto-oncogenes. PRL-induced stimulation of ODC, c-myc, and max mRNAs also was depressed in neonates placed with an anesthetized lactating dam (touch-deprived) but not in pups placed with nipple-ligated dams (food-deprived). Furthermore, unlike its effect on preweanling-age pups (< 20 d old), MS did not alter expression of either ODC or c-myc mRNAs in 25-d-old pups acutely separated from their mother. These findings indicate that suppression of ODC gene transcription in the neonatal pup during MS may be mediated by downregulation of the ODC gene transactivator proto-oncogenes c-myc and max. They are also consistent with our previous observation that lack of maternal touch, but not maternal milk, initiates the physiological alterations induced by MS.

Analysis of Variance↗

PubMed1996

Inhibition of GH in maternal separation may be mediated through altered serotonergic activity at 5-HT2A and 5-HT2C receptors.

The hyposecretion of growth hormone (GH) in maternal separation (MS) of rat pups is remarkably similar to the specific suppression of GH secretion to evocative tests in infants diagnosed with Reactive Attachment Disorder of Infancy (RADI). Growth hormone-releasing factor (GRF) and somatostatin (SS) provide opposing regulation of GH secretion, and both are modified by noradrenergic and serotonergic stimuli in neonatal and adult rats. In this study, GRF administration reversed MS-induced suppression of GH secretion in 10-day-old pups, but this action of GRF was prevented by pretreatment with cyproheptadine (Cypro), a serotonergic antagonist. The normalization of GH secretion after return to the dam was not altered by pretreatment with SS. Indirect 5-HT agonists, fluoxetine (FLX) and 5-HTP, both stimulated GH secretion in 10-day-old pups. All mixed serotonin- and 5-HT1A-receptor agonists suppressed GH secretion in 10-day-old pups. Antagonists Cypro and ketanserin (Ket) suppressed FLX-induced GH secretion. In contrast, only Cypro suppressed 5-HTP-induced GH secretion. Maternal separation inhibited GH secretion stimulated by 5-HTP, but not by FLX. The serotonergic pathway acting on 5-HT2A receptors may be obligatory for GRF-mediated stimulation and is sensitive to inhibition by Cypro. In addition, a Ket-sensitive serotonergic parallel pathway acting on 5-HT2C receptors may also stimulate GH secretion by acting on GRF or SS. However, only the obligate 5-HT2A pathway appears to be suppressed in MS. These data and observations by others indicate that specific suppression of GH secretion in MS may derive from a reduction in GRF release through noradrenergic neurons, possibly impinging upon serotonergic terminals in the hypothalamus. This study may also provide insight into mechanisms by which GH secretion is suppressed in humans with RADI.

Animals↗

PubMed1995

Norepinephrine metabolism and psychoactive drugs in the endogenous depressions. 1968.

After intraventricular injection of norepinephrine-H3, the concentration of norepinephrine, of normetanephrine and of the deaminated catechols in rat brains was determined, following action of imipramine, desmethylimipramine, chlorpromazine, lithium chloride or cocaine. Following administration of imipramine, desmethylimipramine, and chlorpromazine, norepinephrine concentration decreased significantly at first, had distinctly increased 4.5 hours after imipramine and desmethylimipramine but was normal once again after chlorpromazine. Normetanephrine concentration increased after imipramine and desmethylimipramine but was unchanged after chlorpromazine. Under the effect of these drugs, the deaminated catechols showed no changes compared with control values. Cocaine resembled the antidepressants, but the amount of deaminated compounds was reduced. Lithium chloride, on the other hand, increased the concentration of deaminated catechols under certain conditions, reduced normetanephrine concentration but did not influence norepinephrine concentration. In addition to the animal experiments, the following data of six patients with an "endogenous" depression were recorded over a period of several weeks: the clinical findings by means of the Hamilton Depression Rating Scale, and the excretion of normetanephrine and of vanillylmandelic acid (VMA) in the urine before, during and after treatment with imipramine. The therapy led to a significant reduction of VMA; however, this reduction cannot be correlated with an improvement in the clinical findings. On the other hand, excretion of normetanephrine is apparently not dependent on the administration of imipramine but seems to reflect the clinical state, since improvement of the depression was regularly combined with an increased excretion of normetanephrine.

Animals↗

PubMed1994

The inhibition of liver ornithine decarboxylase expression in neonatal rats by maternal separation or CNS beta-endorphin is independent of the pituitary.

Previously we have shown, in rat pups, that either short-term maternal separation (MS) or central (but not peripheral) administration of beta-endorphin (BE) markedly decreases basal levels of ornithine decarboxylase (ODC) activity throughout the body and suppresses liver ODC responsiveness to injected growth hormone (GH). In this study, hypophysectomized (hypox) pups were used to determine whether the pituitary mediates these effects. Hypophysectomy clearly did not prevent the inhibitory actions of MS or intracisternal (i.c.) BE on liver ODC gene expression. The inability of GH to stimulate ODC activity in hypox animals exposed to MS or given BE i.c. is not due to nutritional deprivation, as glucose supplementation did not reverse the response. The results from these studies demonstrate that the pituitary is not the conduit by which either MS or centrally-administered BE regulates liver ODC activity. Also, they support the hypothesis that BE or an analogous opioid neuropeptide is a prime organizer within the CNS of the adaptive physiological response of neonatal rats to short-term MS. As we have previously shown that autonomic neuronal pathways are not involved in the effects of MS on peripheral tissues, the data obtained suggest that increased activity of this CNS opioid system during MS triggers the release of "neurochemicals" into the bloodstream capable of suppressing growth in the mammalian neonate.

Adaptation, Physiological↗

PubMed1993

Maternal separation in neonatal rats elicits activation of the hypothalamic-pituitary-adrenocortical axis: a putative role for corticotropin-releasing factor.

Stress elicits activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Hypothalamic neurohormones, including corticotropin-releasing factor (CRF), control and promote ACTH secretion and subsequent glucocorticoid synthesis and release. The neonatal rat has been shown to be relatively hyporesponsive to certain stressors, generating a blunted or unmeasurable hormonal response. In this study, the endocrine response of 10- and 18-day-old Sprague-Dawley rat pups to maternal separation, a naturalistic stressor, was examined. Ten-day pups subjected to maternal separation exhibited a significant reduction in median eminence CRF concentration at 24 h, with no change in pituitary CRF receptor number; in 18-day pups there was no significant change in median eminence CRF concentration by 24 h, but there was a decrease in CRF receptor binding. In adult rats subjected to stressors, an acute decrease in CRF concentration in the median eminence occurs, followed by CRF receptor downregulation with sustained stress. The results observed in the 18-day pups vs. the 10-day pups likely reflects a maturation of the HPA axis response to "stressors."

Animals↗

PubMed1993

Factors that predict which preterm infants benefit most from massage therapy.

Ninety-three preterm infants (M gestational age = 30 wks; M birth weight = 1204 g; M ICU duration = 15 days) were randomly assigned to a massage therapy group or a control group once they were considered medically stable. The treatment group (N = 50) received three daily 15-minute massages for 10 days. The massage therapy infants gained significantly more weight per day (32 vs 29 g) than did the control infants. Treatment and control groups were divided into high and low weight gainers based on the average weight gain for the control group. Seventy percent of the massage therapy infants were classified as high weight gainers whereas only 40% of the control infants were classified as high weight gainers. Discriminant function analyses determining the characteristics that distinguished the high from the low weight gainers suggested that the control infants who, before the study, consumed more calories and spent less time in Intermediate care gained more weight. In contrast, for the massage therapy group, the pattern of greater caloric intake and more days in Intermediate care before the study period along with more obstetric complications differentiated the high from the low weight gainers, suggesting that the infants who had experienced more complications before the study benefitted more from the massage therapy. These variables accurately predicted 78% of the infants who benefitted significantly from the massage therapy. Thus, these variables can be used to suggest infants who would benefit most from future massage therapy programs.

Birth Weight↗

PubMed1992

Accentuated vagal antagonism of beta-adrenergic effects on ventricular repolarization. Evidence of weaker antagonism in hostile type A men.

BACKGROUND: Prior research has suggested a weaker parasympathetic antagonism of sympathetic effects on the heart in type A (coronary-prone) men. To confirm this phenomenon and extend our understanding of it, we investigated the effects of prior muscarinic blockade on the electrocardiogram T wave and other cardiovascular and neuroendocrine responses to isoproterenol in type A and type B (non-coronary-prone) men. METHODS AND RESULTS: Responses to two 5-minute intravenous isoproterenol infusions (0.01 micrograms/kg/min and 0.02 micrograms/kg/min) were evaluated in six type A and six type B men after pretreatment with either dextrose placebo or atropine (1.2 mg). Atropine significantly potentiated T wave attenuation in the recovery period after isoproterenol infusion (0.30 +/- 0.07 mV) compared with placebo (0.54 +/- 0.09 mV, p less than 0.001). Atropine also potentiated the heart rate increase to isoproterenol (39 +/- 3 beats per minute versus 20 +/- 2 beats per minute after placebo). Atropine enhanced decreases in systolic, diastolic, and mean arterial pressures as well as pulse pressure to isoproterenol. Atropine enhancement of many of these responses was increased among subjects with high scores on various hostility/anger scales. Isoproterenol alone produced greater T wave attenuation in type A than in type B men. However, atropine enhancement of T wave attenuation and blood pressure falls by isoproterenol was present only in type B men. CONCLUSIONS: These findings indicate that there is accentuated parasympathetic antagonism of T wave attenuation and blood pressure responses induced by beta-adrenergic stimulation. Relative weakness of this antagonism of sympathetic effects on the heart in hostile type A individuals may contribute to their higher coronary disease risk.

Adult↗

PubMed1991

Further evidence for the hypothesis that beta-endorphin mediates maternal deprivation effects.

Lung DNA synthesis was examined in 9-day-old rat pups following a 2-hour separation from their mothers (maternal deprivation), and compared to that of pups placed with a nipple ligated dam (food deprivation) or a lactating dam (control). Maternally deprived pups consistently showed a significant reduction in lung DNA synthesis which was not attributable to food deprivation. Central administration of naloxone prevented the decrease in DNA synthesis observed after maternal deprivation but did not inhibit the reductions in lung DNA synthesis seen two hours after sc administration of isoproterenol, suggesting that DNA response to maternal deprivation is a specific opioid receptor mediated event. These results are consistent with previous reports from our laboratory indicating that CNS beta-endorphin may mediate many of the biological alterations observed following maternal deprivation in neonatal rats.

Animals↗

PubMed1991

Effects of central administration of beta-endorphin on brain and liver DNA synthesis in preweanling rats.

We have previously shown that central administration of beta-endorphin results in a reduction of ornithine decarboxylase activity. Ornithine decarboxylase catalyses the rate-limiting step in the biosynthesis of the polyamines putrescine, spermidine and spermine, thought to modulate nucleic acid synthesis. The present study examines the effects of intracisternal injection of beta-endorphin on brain and liver DNA synthesis in preweanling rats. In six-day-old rats, beta-endorphin (0.75 micrograms/g brain wt) produced approximately a 70% inhibition in brain and liver DNA synthesis 1 h after injection, and values were still subnormal in both tissues 10 h later. Subcutaneous administration of beta-endorphin did not alter liver DNA synthesis. Thus, it is most likely that the suppressed liver DNA synthesis observed in animals given beta-endorphin intracisternally is mediated by central mechanisms. Co-administration of naloxone plus beta-endorphin intracisternally prevented the response, indicating an opioid receptor-mediated phenomenon. Naloxone alone caused small but significant increases in brain and liver DNA synthesis, suggesting a tonic influence on tissue DNA by endogenous opioids in the CNS. Acute inhibition of ornithine decarboxylase activity by alpha-difluoromethylornithine did not alter DNA synthesis, indicating that the decreases in DNA synthesis induced by beta-endorphin are unrelated to the ornithine decarboxylase/polyamine system. The effect appears to be restricted to early development as no significant changes in DNA synthesis were obtained in 20-day-old animals. The results from these studies indicate that CNS beta-endorphin has the ability to influence DNA synthesis in central as well as in peripheral tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Tactile-kinesthetic stimulation effects on sympathetic and adrenocortical function in preterm infants.

The purpose of our study was to investigate the neuroendocrine response in preterm infants to a pattern of tactile-kinesthetic stimulation that facilitates their growth and development. Preterm infants (mean gestational age 30 weeks, mean birth weight 1176 gm) received normal nursery care or tactile-kinesthetic stimulation for three 15-minute periods at the start of three consecutive hours each day for 10 days. On day 1 and day 10 of the study, a 24-hour urine sample was collected for norepinephrine, epinephrine, dopamine, cortisol, and creatinine assay and a blood sample was taken by heel stick for cortisol and growth hormone assay. Urine norepinephrine and epinephrine values increased significantly only in the stimulated babies. Urine dopamine and cortisol values increased in both groups, and serum growth hormone decreased in both groups. Individual differences in urine norepinephrine, epinephrine, dopamine, and cortisol values were highly stable across the 10 days despite a 10-fold range of values among the infants. The results of this study suggest that tactile-kinesthetic stimulation of preterm infants has fairly specific effects on maturation and/or activity of the sympathetic nervous system. In addition, this study has defined catecholamine and cortisol secretion across gestational age in normal preterm infants. Finally, these data suggest that highly stable individual levels of catecholamine and cortisol secretion are established by birth in humans.

Creatinine↗

PubMed1991

Effect of central administration of beta-endorphin on lung ornithine decarboxylase activity in developing rats.

Results from a number of studies suggest a role for endogenous opioids in the regulation of lung development and function. Although it is not known which opioid peptides are involved in these processes, accumulated evidence suggests a prominent role for beta-endorphin (BE). Our study examines the effect of BE on lung ornithine decarboxylase (ODC) activity in preweanling rats. ODC catalyzes the rate-limiting step in the synthesis of the polyamines spermidine and spermine, key regulators of cell growth, multiplication, and differentiation. Central (but not peripheral) administration of BE reduced lung ODC activity by as much as 80% in the 6-d-old rat. Significant decreases in ODC activity were seen at doses of BE as low as 0.5 micrograms/g brain wt. In contrast to the reductions in ODC activity, plasma levels of corticosterone in animals administered BE were approximately five times higher than those seen in control animals. BE's actions on ODC activity and plasma corticosterone levels were prevented by naloxone or naltrexone, indicating that both responses are mediated by opioid receptors. Studies of ODC kinetics showed a profound reduction in Vmax (70% below control values), but no change in Km. The effect was observed only during the first 2 wk of postnatal age, a period of time in lung maturation that is characterized by active alveolarization. Because changes in ODC levels during early postnatal life are associated with perturbations in tissue growth and/or function, the data suggest that CNS BE may influence lung maturation through an indirect action that may involve glucocorticoids.

Age Factors↗

PubMed1991

Alterations in cardiovascular responsiveness and adrenoceptor binding during catecholamine infusion hypertension in rats.

Chronic continuous infusion of norepinephrine in rats causes alterations in biochemical and physiologic responses of the cardiovascular system and in cardiovascular adrenoceptor number. The response of cardiac and aortic ornithine decarboxylase (ODC) activity to stimulation by norepinephrine was decreased in rats receiving norepinephrine infusion. These responses are due to stimulation of beta- and alpha-adrenergic receptors, respectively. Additionally, there was reduced stimulation of aortic ODC activity by angiotensin II and vasopressin. The cardiac ODC response to angiotensin II was decreased, but the response to vasopressin was not affected. The decreased ODC response is accompanied by decreased pressor responses to the alpha-adrenergic agonist phenylephrine. Decreased numbers of alpha- and beta-adrenoceptor binding sites (as measured by the binding of [3H]prazosin and [125I]pindolol) might mediate, in part, the altered responses to adrenergic agonists. The decreased cardiovascular responsiveness measured in these animals after several days of norepinephrine infusion hypertension contrasts with the increased responses found in most other forms of hypertension. This provides a useful model in which to examine the consequences of prolonged adrenergic receptor stimulation.

Angiotensin II↗

PubMed1990

Endocrine responses to mother-infant separation in developing rats.

Separation of neonatal rat pups from the dam have been reported to elicit two endocrine responses in the pup: a fall in growth hormone secretion and a rise in corticosterone secretion. However, the temporal, ontogenetic, and behavioral determinants of these responses have not been compared. In the present study, we report that these two responses can be differentiated on each of these criteria. Growth hormone secretion falls rapidly immediately upon separation of pups from the dam, while robust rises in corticosterone secretion are delayed for many hours. In addition, growth hormone responses are observed earlier in ontogeny. Finally, active maternal behavior is required for normal growth hormone secretion in 10-day-old rat pups, while passive sensory stimuli associated with the dam can significantly reduce the corticosterone response to separation.

Animals↗

PubMed1990

Corticotropin-releasing factor concentrations exhibit an apparent diurnal rhythm in hypothalamic and extrahypothalamic brain regions: differential sensitivity to corticosterone.

Regional brain concentrations of corticotropin-releasing factor (CRF) exhibited marked differences in a number of regions depending upon the time of day rats were sacrificed. When compared with animals killed at 09.00 h, CRF concentrations at 15.30 h were elevated in the median eminence, hypothalamus minus median eminence, preoptic area/suprachiasmatic nucleus, bed nucleus of the stria terminalis, septum, frontal/parietal cortex, cerebellum, cingulate cortex, locus ceruleus and the nucleus of the solitary tract. Animals that received 7 days of continuous corticosterone supplementation via osmotic minipump either did not exhibit an afternoon rise in CRF concentrations (median eminence, cingulate cortex and locus ceruleus) or exhibited significantly attenuated afternoon increases in CRF concentrations (hypothalamus minus median eminence). In rats killed at 09.00 h, corticosterone reduced CRF concentrations in the median eminence. Chronic corticosterone exposure did not affect CRF concentrations in any of the extrahypothalamic brain regions studied in rats killed at 09.00 h. These results suggest that a number of CRF-containing neurons in both hypothalamic and extrahypothalamic brain regions presumably undergo diurnal changes in their activity as evidenced by changes in CRF concentrations. Furthermore, chronic corticosterone supplementation can alter these changes, particularly those in the endocrine hypothalamus.

Animals↗