Gloria Levin

Characteristics of pheochromocytoma in a 4- to 20-year-old population.

Abstract:  Hypertension in children and adolescents has become a major health problem recently recognized, and in a significant number of patients it is due to an endocrine tumor. The aim of this study was to establish the characteristics of pheochromocytoma in a population of 58 patients between 4 and 20 years of age studied at our Center. They represented a 23% of the total population of 255 pheochromocytoma patients studied. In the younger group (under 20 years of age), there was a marked predominance of severe sustained hypertension (93%), only 7% presented paroxysmal hypertension and none of them was normotensive. The youngsters studied showed a higher incidence of bilateral adrenal pheochromocytoma (34%) and extra‐adrenal pheochromocytoma (22%). Malignancy was found in 12% of these patients. In addition, the incidence of familial pheochromocytoma was elevated in these patients (39%). Surprisingly, in contrast with the adult population where the most frequent familial pheochromocytomas were multiple endocrine neoplasia (MEN) type 2A (15%), the younger population showed a higher predominance of von Hippel–Lindau (VHL) (28%) and lower incidence of MEN 2A, MEN 2B, neurofibromatosis (NF), and succinate dehydrogenase subunit B (SDHB). In the VHL group, only two patients belonging to one family, showed the R167W mutation, while the others showed novel mutations in conserved amino acids. It may be speculated that the high incidence of VHL in youngsters may account for the biochemical and clinical features they usually present.

Sex differences in rats: Effects of chronic stress on sympathetic system and anxiety

In this study we tested whether periodic maternal deprivation (MD) (4.5 h daily during the first 3 weeks of life) caused chronic changes in anxiety and medullo-adrenal responses to chronic stress in either male or female adult (2.5 months of age) rats, or both. Repeated maternal deprivation had a sex-specific effect on epinephrine (E) and norepinephrine (NE) levels: an increase in both measures was observed only in females. Unpredictable stress did not produce changes on plasma catecholamine levels either in males or females. However, when the females were maternally deprived as well as stressed they showed an increase in plasma NE p < 0.05. On the other hand, non-maternally deprived (NMD), maternally-deprived and stressed males showed high levels of catecholamines compared to females p < 0.001. In the elevated plus maze test, MD-treated males displayed a slight increase in anxiety-related behavior compared with NMD rats. This was indicated by a reduction in the time spent on the open arms, whereas females showed less anxiety, indicated by an increase in the number of entries, and in the time spent on the open arms. After exposure to chronic stress only the females displayed decreased anxiety-related behavior. These results suggest that there are sex-induced effects in emotional reactivity, perception of the stressor and in the evaluation of novel situations. Thus, maternal deprivation and chronic variable stress caused both long-term alterations in sympathetic response and gender-dependent changes in the anxiety index of adult rats.

Peripheral catecholamine alterations in adolescents with polycystic ovary syndrome

Polycystic ovary syndrome (PCO) is one of the most common endocrine disorders affecting women. Several lines of evidence have suggested the involvement of the sympathetic nervous system (SNS) in this condition. The present work was designed to assess neurochemically SNS activity in patients during the early stages of PCO.

Stress increases endogenous benzodiazepine receptor ligand-monoamine oxidase inhibitory activity (tribulin) in rat tissues

The presence of both MAO and benzodiazepine (BZ) receptor binding inhibitory activities in rat tissues has been reported previously. The two activities were similarly and unevenly distributed in the tissues. This dual inhibitory activity has been termed tribulin. We report here the effect of 1 1/2 hrs cold restraint stress on tribulin activity in rat tissues together with biochemical evidence to support the concept of a physiological role of tribulin. Stress induced a significant increment of both activities in heart and kidney while no significant changes were observed in the other tissues studied. Hearts and kidneys from stressed rats also showed a significant decrease of MAO activity, a significant increase of dopamine content and a significant decrease of the binding of3H-Ro 5-4864 to peripheral BZ receptors. Scatchard analysis of the saturation curves carried out using3H-Ro 5-4864 (0.4–10 nM) showed significant Bmax decreases in both organs. No significant change in either of these inhibitory activities was observed in the other tissues studied. These data provide support for a role of tribulin in the biochemical response to stress.

Periodic maternal deprivation and lesion of anterodorsal thalami nuclei induce alteration on hypophyso adrenal system activity in adult rats.

The hypothalamic-pituitary-adrenal (HPA) axis is normally regulated by extrahypothalamic limbic structures, among these, the anterodorsal thalami nuclei (ADTN), which exert an inhibitory influence on HPA, in basal and acute stress conditions in rats. In the present work we have investigated whether neonatal maternal deprivation (MD) produces long-term changes in the ADTN regulation of HPA activity. Maternal deprivation, in female rats, for 4.5 hs daily, during the first 3 weeks of life, produced at 3 months old, a significant decrease in plasma ACTH concentration (p<0.001) and an increase in plasma corticosterone (C) (p<0.001), compared to control non-deprived rats (NMD). Also MD showed higher plasma epinephrine (E) and norepinephrine (NE) levels than NMD rats. The increase of NE (66.6% p<0.001) was higher than that observed in E (19%). After 30 days of ADTN lesion, plasma ACTH values were higher than in sham lesioned rats, in both NMD and MD animals. ACTH response was greater in MD rats. Plasma C, in NMD, was higher, whereas in MD lesioned animals, it was significantly lower than in sham lesioned. In MD rats, lesion produced a significant increase in plasma E and NE (p<0.001), and again, NE increase was higher than E increase. The more accentuated increase of NE than E, suggests sympathetic nervous system hyperactivity. In summary, neonatal maternal deprivation induces long-term alterations on HPA axis sensitivity and medullo adrenal secretion; enhanced sympathetic nervous system activity and, therefore affected the ADTN inhibitory influence on ACTH and adrenal glands secretion.

Involvement of dopamine signaling in the circadian modulation of interval timing

Duration discrimination within the seconds‐to‐minutes range, known as interval timing, involves the interaction of cortico‐striatal circuits via dopaminergic–glutamatergic pathways. Besides interval timing, most (if not all) organisms exhibit circadian rhythms in physiological, metabolic and behavioral functions with periods close to 24 h. We have previously reported that both circadian disruption and desynchronization impaired interval timing in mice. In this work we studied the involvement of dopamine (DA) signaling in the interaction between circadian and interval timing. We report that daily injections of levodopa improved timing performance in the peak‐interval procedure in C57BL/6 mice with circadian disruptions, suggesting that a daily increase of DA is necessary for an accurate performance in the timing task. Moreover, striatal DA levels measured by reverse‐phase high‐pressure liquid chromatography indicated a daily rhythm under light/dark conditions. This daily variation was affected by inducing circadian disruption under constant light (LL). We also demonstrated a daily oscillation in tyrosine hydroxylase levels, DA turnover (3,4‐dihydroxyphenylacetic acid/DA levels), and both mRNA and protein levels of the circadian component Period2 (Per2) in the striatum and substantia nigra, two brain areas relevant for interval timing. None of these oscillations persisted under LL conditions. We suggest that the lack of DA rhythmicity in the striatum under LL – probably regulated by Per2 – could be responsible for impaired performance in the timing task. Our findings add further support to the notion that circadian and interval timing share some common processes, interacting at the level of the dopaminergic system.

Evaluation of sympathetic nervous system and adrenomedullary activity in normal children

In 22 healthy children heart rate, blood pressure and plasma levels of epinephrine (E) and norepinephrine (NE) were evaluated under basal conditions and in response to standing (5 min). Basal plasma E and NE levels found in these children were (means +/- S.E.M.) 139 +/- 17.9 pg/ml and 236 +/- 31.0 pg/ml respectively. Ten out of the 22 children reported dizziness and discomfort by the end of the 5 min standing period. These children showed not only a greater decrease in both systolic and diastolic blood pressure but also a lower basal heart rate, a tendency to higher basal NE levels and a blunted plasma NE response (23 +/- 7%) when compared with children not reporting symptoms (60 +/- 9%, P less than 0.01). Plasma E levels also showed an increment although a wide range of individual responses was observed in both groups.

Long-term effects of maternal separation on chronic stress response suppressed by amitriptyline treatment

Abstract The early-life environment has many long-term effects on mammals. Maternal interaction and early stressful events may affect regulation of the HPA axis during adulthood, leading to differential glucocorticoid secretion in response to stressful situations. These adverse experiences during postnatal development may even sensitize specific neurocircuits to subsequent stressors. Later in life, the overreaction of the HPA axis to stress can constitute a risk factor for metabolic and mental diseases. As tricyclic antidepressants are known to correct glucocorticoid hypersecretion during depression, we treated maternally separated animals with amitriptyline, at a lower dose than habitually used in depression models, to prevent the response to chronic stress during adulthood. Male Wistar rats were separated from the mother for 4.5 h every day for the first 3 weeks of life. From postnatal day 50, animals were subjected to chronic variable stress during 24 d (five types of stressors at different times of day). During the stress, protocol rats were orally administered amitriptyline (5 mg/kg) daily. We observed that maternal separation caused a reduction in plasma ACTH levels (p < 0.05), but evoked hypersecretion of corticosterone (p < 0.05) when it was combined with stress in adulthood. This rise was completely prevented by antidepressant treatment with amitriptyline.

Amitriptyline Treatment Under Chronic Stress Conditions: Effect on Circulating Catecholamines and Anxiety in Early Maternally Separated Rats

The aim of this work was to determine the effect of amitriptyline (AMI) on peripheral outcomes such as plasma epinephrine (E) and norepinephrine (NE) concentration and anxiety-like behavior displayed in the plus maze test in adult male Wistar rats under variable chronic stress and daily oral administration of AMI (5 mg/kg). Animals were previously isolated from the mother for 4.5 hr every day for the first 3 weeks of life. Administration of the antidepressant AMI reduced anxiety-like behavior in animals submitted only to chronic stress but not in early maternally separated (MS) subjects or in animals subjected to the two types of stresses.

The Role of the Anterodorsal Thalami Nuclei in the Regulation of Adrenal Medullary Function, Beta-adrenergic Cardiac Receptors and Anxiety Responses in Maternally Deprived Rats under Stressful Conditions

Maternal separation can interfere with growth and development of the brain and represents a significant risk factor for adult psychopathology. In rodents, prolonged separation from the mother affects the behavioral and endocrine responses to stress for the lifetime of the animal. Limbic structures such as the anterodorsal thalamic nuclei (ADTN) play an important role in the control of neuroendocrine and sympathetic-adrenal function. In view of these findings we hypothesized that the function of the ADTN may be affected in an animal model of maternal deprivation. To test this hypothesis female rats were isolated 4.5 h daily, during the first 3 weeks of life and tested as adults. We evaluated plasma epinephrine (E) and norepinephrine (NE), cardiac adrenoreceptors and anxiety responses after maternal deprivation and variable chronic stress (VCS) in ADTN-lesioned rats. Thirty days after ADTN lesion, in non-maternally deprived rats basal plasma NE concentration was greater and cardiac β-adrenoreceptor density was lower than that in the sham-lesioned group. Maternal deprivation induced a significant increase in basal plasma NE concentration, which was greater in lesioned rats, and cardiac β-adrenoreceptor density was decreased in lesioned rats. After VCS plasma catecholamine concentration was much greater in non-maternally deprived rats than in maternally-deprived rats; cardiac β-adrenoreceptor density was decreased by VCS in both maternally-deprived and non-deprived rats, but more so in non-deprived rats, and further decreased by the ADTN lesion. In the plus maze test, the number of open arm entries was greater in the maternally deprived and in the stressed rats. Thus, sympathetic-adrenal medullary activation produced by VCS was much greater in non-deprived rats, and was linked to a down regulation of myocardial β-adrenoceptors. The ADTN are not responsible for the reduced catecholamine responses to stress in maternally-deprived rats. Maternal deprivation or chronic stress also induced a long term anxiolytic effect, which was also not affected by ADTN lesion.