Aspartic acid administered neonatally affects ventilation of male and female rats differently

In this study ventilation was evaluated in 12-mo-old male and female rats who had received large doses of aspartic acid neonatally. Rats of both sexes treated with aspartic acid were obese, stunted, and exhibited hypogonadism. Although metabolic rates of the aspartic acid-treated rats were not different compared with sex-matched controls, ventilatory patterns were different. Aspartic acid-treated females breathed with a smaller tidal volume (VT), higher frequency (f), and similar minute ventilation (VE) compared with control females. This pattern is commonly observed in many patients who are obese. The aspartic acid-treated females responded to hypercapnic and hypoxic challenges by increasing f more than VT. Tissue pocket gases (PCO2 and PO2) of aspartic acid-treated females were normal. In contrast, aspartic acid-treated males hypoventilated compared with control males. Tissue pocket gas values suggested that aspartic acid-treated males were hypoxemic and hypercapnic. Moreover, the response of aspartic acid-treated males to hypercapnia was parallel to but was less than that of control male rats. The ventilatory response of aspartic acid-treated male rats to hypoxia was blunted. This study has shown that neonatal administration of aspartic acid causes a decreased ventilation and blunted response to hypoxia in adult male but not female rats.     

Dextromethorphan affects ventilation differently in male and female rats

Schlenker, Evelyn H. Dextromethorphan affectsventilation differently in male and female rats. J. Appl.Physiol. 81(5): 1911-1916, 1996.Subcutaneous administrationof aspartic acid results in a long-lasting but reversible depression ofventilation in male but not in female rats. Aspartic acid acts onN-methyl-D-aspartate receptors. The present studytested the hypothesis that a noncompetitive N-methyl-D-aspartate-receptor antagonist,dextromethorphan (Dex), would depress ventilation in female rats andstimulate it in male rats. Moreover, Dex administered prior to asparticacid should prevent the aspartic acid-induced depression of ventilationin male rats. In female rats, Dex caused a 30% depression ofventilation relative to saline at 5 and 10 mg/kg (P < 0.01)but not at the highest dose (20 mg/kg). In male rats, Dex had no effecton ventilation. At a dose of 20 mg/kg, Dex depressed oxygen consumptionto 50% of the saline value at all time points in female rats(P < 0.001) and in male rats 45 and 60 minafter administration. The time points when Dex depressed ventilationand oxygen consumption were different in female rats, suggesting thatthe depression of ventilation was not the result of a depression inoxygen consumption. During a hypercapnic challenge (7%CO₂), female rats treated with 5 and 10 mg/kg of Dexexhibited a smaller increase in ventilatory response relative to salinetreatment. At a dose of 20 mg/kg, the hypercapnic responsiveness ofmale rats was markedly stimulated (85.8 ± 8.95 ml/min) relative tosaline (50.6 ± 9.14 ml/min; P < 0.001). Finally, Dexadministered before aspartic acid prevented the aspartic acid-induced depression of ventilation in male rats. Thus, in rats, Dex has gender-specific effects on ventilation and these effects are not associated with changes in oxygen consumption.

     

Somatostatin inhibits the ventilatory response to hypoxia in humans

The effects of a 90-min infusion of somatostatin (1 mg/h) on ventilation and the ventilatory responses to hypoxia and hypercapnia were studied in six normal adult males. Minute ventilation (VE) was measured with inductance plethysmography, arterial 02 saturation (SaO2) was measured with ear oximetry, and arterial PCO2 (Paco2) was estimated with a transcutaneous CO2 electrode. The steady-state ventilatory response to hypoxia (delta VE/delta SaO2) was measured in subjects breathing 10.5% O2 in an open circuit while isocapnia was maintained by the addition of CO2. The hypercapnic response (delta VE/delta PaCO2) was measured in subjects breathing first 5% and then 7.5% CO2 (in 52-55% O2). Somatostatin greatly attenuated the hypoxic response (control mean -790 ml x min-1.%SaO2 -1, somatostatin mean -120 ml x min-1.%SaO2 -1; P less than 0.01), caused a small fall in resting ventilation (mean % fall - 11%), but did not affect the hypercapnic response. In three of the subjects progressive ventilatory responses (using rebreathing techniques, dry gas meter, and end-tidal Pco2 analysis) and overall metabolism were measured. Somatostatin caused similar changes (mean fall in hypoxic response -73%; no change in hypercapnic response) and did not alter overall O2 consumption nor CO2 production. These results show an hitherto-unsuspected inhibitory potential of this neuropeptide on the control of breathing; the sparing of the hypercapnic response is suggestive of an action on the carotid body but does not exclude a central effect.     

Local application of somatostatin in the rat ventrolateral brain medulla induces apnea

Local injections of the tetradecapeptide somatostatin (SOM) into the brain stem region were performed in anesthetized and decerebrate rats. SOM administration (0.6-1.8 nmol) into the nucleus paragigantocellularis and the nucleus reticularis lateralis of the ventrolateral medulla oblongata induced ventilatory depression and apnea. The occurrence of apnea was dose dependent and attributed to the anesthetic depth, and it was seen within 60-240 s after injection. In anesthetized rats the apnea was seen as a termination or a continuous decrease in tidal volume while respiratory frequency remained unaltered. SOM-induced apnea was caused by depression of central inspiratory drive. SOM injections into the dorsal medulla were ineffective in eliciting apnea, although a ventilatory depression but no apnea was induced in the awake unanesthetized state. In addition to its effect on basal ventilation, SOM administration in the ventrolateral medulla resulted in a blunted ventilatory response to hypoxic and hypercapnic stimuli in anesthetized rats. We conclude that SOM has potent inhibitory effects on respiration that are specifically located in the nucleus paragigantocellularis and the nucleus reticularis lateralis.     

Ventilatory response to sustained hypoxia in carotid body denervated rats

Hypoxia stimulates ventilation, but when it is sustained, a decline in the ventilatory response is seen. The mechanism responsible for this decline lies within the CNS, but still remains unknown. In this study, we attempted to elucidate the possible role of hypoxia-induced depression of respiratory neurons by comparing the ventilatory response to hypoxia in intact rats and those with denervated carotid bodies. A whole-body plethysmograph was used to measure tidal volume, frequency of breathing and minute ventilation (VE) in awake and anesthetized intact rats and rats after carotid body denervation during exposure to hypoxia (FIO2 0.1). Fifteen-minute hypoxia induced an initial increase of VE in intact rats (to 248% of control ventilation in awake and to 227% in anesthetized rats) followed by a consistent decline (to 207% and 196% of control VE, respectively). Rats with denervated carotid bodies responded with a smaller increase in VE (to 134% in awake and 114% in anesthetized animals), but without a secondary decline (145% and 129% of control VE in the 15th min of hypoxia). These results suggest that afferentation from the carotid bodies and/or the substantial increase in ventilation are crucial for the biphasicity of the ventilatory response to sustained hypoxia and that a central hypoxic depression cannot fully explain the secondary decline in VE.     

GABAergic modulation of ventilation and peak oxygen consumption in obese Zucker rats.

Obesity is often associated with a reduced ventilatory response and a decreased maximal exercise capacity. GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. Altered GABAergic mechanisms have been detected in obese Zucker rats and implicated in their hyperphagic response. Whether altered GABAergic mechanisms also contribute to regulate ventilation and influence exercise capacity in obese Zucker rats is unknown and formed the basis of the present study. Eight lean [317 +/- 18 (SD) g] and eight obese (450 +/- 27 g) Zucker rats were studied at 12 wk of age. Ventilation at rest and ventilation during hypoxic (10% O(2)) and hypercapnic (4% CO(2)) challenges were measured by the barometric method. Peak O(2) consumption (VO(2 peak)) in response to a progressive treadmill test to exhaustion was measured in a metabolic treadmill. Ventilation and VO(2 peak) were assessed after administration of equal volumes of DMSO (vehicle) and the GABA(A) receptor antagonist bicuculline (1 mg/kg). In lean animals, bicuculline administration had no effect on ventilation and VO(2 peak). In obese rats, bicuculline administration significantly (P < 0.05) increased resting ventilation (465 +/- 53 and 542 +/- 72 ml. kg(-1). min(-1) for control and bicuculline, respectively), ventilation during exposure to hypoxia (899 +/- 148 and 1,038 +/- 83 ml. kg(-1). min(-1) for control and bicuculline, respectively), and VO(2 peak) (62 +/- 3.7 and 67 +/- 3.5 ml. kg(-0.75). min(-1) for control and bicuculline, respectively). However, in obese Zucker rats, ventilation in response to hypercapnia did not change after bicuculline administration (608 +/- 96 vs. 580 +/- 69 ml. kg(-1). min(-1)). Our findings indicate that endogenous GABA depresses ventilation and limits exercise performance in obese Zucker rats.     

Effect of hypoxic episode number and severity on ventilatory long-term facilitation in awake rats.

Episodic hypoxia induces a persistent augmentation of respiratory activity, termed long-term facilitation (LTF). Phrenic LTF saturates in anesthetized animals such that additional episodes of stimulation cause no further increase in LTF magnitude. The present study tested the hypothesis that 1) ventilatory LTF also saturates in awake rats and 2) more severe hypoxia and hypoxic episodes increase the effectiveness of eliciting ventilatory LTF. Minute ventilation was measured in awake, male Sprague-Dawley rats by plethysmography. LTF was elicited by five episodes of 10% O(2) poikilocapnic hypoxia (magnitude: 17.3 +/- 2.8% above baseline, between 15 and 45 min posthypoxia, duration: 45 min) but not 12 or 8% O(2). LTF was also elicited by 10, 20, and 72 episodes of 12% O(2) (19.1 +/- 2.2, 18.9 +/- 1.8, and 19.8 +/- 1.6%; 45, 60, and 75 min, respectively) but not by three or five episodes. These results show that there is a certain range of hypoxia that induces ventilatory LTF and that additional hypoxic episodes may increase the duration but not the magnitude of this response.     

Cardiovascular responses to hypoxia and hypercapnia in barodenervated rats

Experiments were performed to examine the role of the arterial baroreceptors in the cardiovascular responses to acute hypoxia and hypercapnia in conscious rats chronically instrumented to monitor systemic hemodynamics. One group of rats remained intact, whereas a second group was barodenervated. Both groups of rats retained arterial chemoreceptive function as demonstrated by augmented ventilation in response to hypoxia. The cardiovascular effects to varying inspired levels of O2 and CO2 were examined and compared between intact and barodenervated rats. No differences between groups were noted in response to mild hypercapnia (5% CO2); however, the bradycardia and reduction in cardiac output observed in intact rats breathing 10% CO2 were eliminated by barodenervation. In addition, hypocapnic hypoxia caused a marked fall in blood pressure and total peripheral resistance (TPR) in barodenervated rats compared with controls. Similar differences in TPR were observed between the groups in response to isocapnic and hypercapnic hypoxia as well. It is concluded that the arterial baroreflex is an important component of the overall cardiovascular responses to both hypercapnic and hypoxic stimuli in the conscious rat.     

Ventilatory and metabolic responses to hypoxia in the smallest simian primate, the pygmy marmoset.

The pygmy marmoset (Cebuella pygmaea) is the smallest New World Monkey (average body mass of 120-130 g). As such, it faces possible challenges to thermoregulation. Small mammals (e.g., rats) are well known to lower body temperature and metabolism in response to hypoxia; however, small primates have not been studied in this respect nor have, in general, the interactions between metabolism and ventilation. Because little is known about these responses in small primates, it seemed of great interest to assess the hypoxia-induced metabolic depression and drop in body temperature and the associated ventilatory requirements in this species under hypoxic conditions. Exposure to graded hypoxia (30 min at each of 18, 16, 14, 12, and 10% O(2)) caused body temperature to drop from the normoxic value of 39 to 37 degrees C. This was accompanied by a marked metabolic depression (O(2) consumption was approximately 68% of the normoxic value, implying a suppression of metabolism greater than that predicted from a typical value of the effect of 10 degrees C change on metabolism of 2-3 times). Minute ventilation declined in parallel to metabolism, maintaining a constant air-convection requirement during hypoxia; thus this species did not show the typical mammalian hyperventilation. Acute exposure to 10% O(2) led to a similar overall decline in metabolism and body temperature and qualitative differences in the timing of these changes. The pygmy marmoset shares some similarities in its hypoxic metabolic response with other mammals of similar size yet appears to be unique in its much diminished ventilatory response to hypoxia.     

Lordosis behavior in castrated male rats treated with estradiol benzoate or testosterone propionate in combination with an estrogen antagonist, MER-25, and in intact male rats

Lordosis behavior could be elicited by manual stimulation in castrated male rats after treatment with estradiol benzoate (15 μg for 10 days) or testosterone propionate (1 or 3 mg for 10 days). The effect was antagonized by treatment with the estrogen antagonist MER-25 (10mg for 10 days). Prolonged treatment with testosterone propionate (1 mg for 26 days) resulted in display of male (nine of ten rats) as well as female (seven of ten rats) sexual behavior. Eleven of 32 intact male rats (age 120 days) and 22 of 37 other intact males (age 75 days) displayed lordosis in response to manual stimulation without hormonal treatment. Seven intact males which showed lordosis without hormone treatment were injected with MER-25 (10 mg/day × 10 days) and lordosis was abolished in six cases. The results suggest that estrogen is involved in the regulation of lordosis behavior in TP-treated and intact male rats.     

Neonatal maternal separation induces sex-specific augmentation of the hypercapnic ventilatory response in awake rat.

Neonatal maternal separation (NMS) is a form of stress that exerts persistent, sex-specific effects on the hypoxic ventilatory response. Adult male rats previously subjected to NMS show a 25% increase in the response, whereas NMS females show a response 30% lower than controls (8). To assess the extent to which NMS affects ventilatory control development, we tested the hypothesis that NMS alters the ventilatory response to hypercapnia in awake, unrestrained rats. Pups subjected to NMS were placed in a temperature- and humidity-controlled incubator 3 h/day for 10 consecutive days (P3 to P12). Control pups were undisturbed. At adulthood (8 to 10 wk old), rats were placed in a plethysmography chamber for measurement of ventilatory parameters under baseline and hypercapnic conditions (inspired CO(2) fraction = 0.05). After 20 min of hypercapnia, the minute ventilation response measured in NMS males was 47% less than controls, owing to a lower tidal volume response (22%). Conversely, females previously subjected to NMS showed minute ventilation and tidal volume responses 63 and 18% larger than controls respectively. Although a lower baseline minute ventilation contributes to this effect, the higher minute ventilation/CO(2) production response observed in NMS females suggests a greater responsiveness to CO(2)/H(+) in this group. We conclude that NMS exerts sex-specific effects on the hypercapnic ventilatory response and that the neural mechanisms affected by NMS likely differ from those involved in the hypoxic chemoreflex.     

Sinoaortic contribution to ventilatory control in exercising dogs

The role of the sinoaortic reflexes in the regulation of ventilation during exercise was evaluated in seven awake dogs prepared with chronic tracheostomies and arterial catheters. Each dog ran on a treadmill at several work loads before and after sinoaortic denervation and served as its own control. Minute ventilation in the sinoaortic denervated state was significantly reduced from intact values by 10-40% at the mild and moderate levels of exercise [O2 uptake (VO2) = 30-50 ml . kg-1 . min-1] mainly as a result of a lowering respiratory frequency. At higher work loads (VO2 = 70-80 ml . kg-1 . min-1) minute ventilation was similar in the intact and denervated states, but the pattern of ventilation was altered with a higher frequency and a lower tidal volume in the denervated state. The rise in ventilation toward a stable plateau was slower at all work loads in the denervated than in the intact state. After sinoaortic denervation, arterial PCO2(PaCO2) levels were significantly elevated above intact PaCO2 levels during both the preexercise period and the steady state at all exercise levels. These results suggest that the sinoaortic reflexes contribute to both the control of ventilation and the pattern of breathing during mild and heavy levels of exercise in the conscious dog.     

Acetazolamide protects against posthypoxic unstable breathing in the C57BL/6J mouse.

Acetazolamide (Acz), a carbonic anhydrase inhibitor, is used to manage periodic breathing associated with altitude and with heart failure. We examined whether Acz would alter posthypoxic ventilatory behavior in the C57BL/6J (B6) mouse model of recurrent central apnea. Experiments were performed with unanesthetized, awake adult male B6 mice (n = 9), ventilatory behavior was measured using flow-through whole body plethysmography. Mice were given an intraperitoneal injection of either vehicle or Acz (40 mg/kg), and 1 h later they were exposed to 1 min of 8% O(2)-balance N(2) (poikilocapnic hypoxia) or 12% O(2)-3% CO(2)-balance N(2) (isocapnic hypoxia) followed by rapid reoxygenation (100% O(2)). Hypercapnic response (8% CO(2)-balance O(2)) was examined in six mice. With Acz, ventilation, including respiratory frequency, tidal volume, and minute ventilation, in room air was significantly higher and hyperoxic hypercapnic ventilatory responsiveness was generally lower compared with vehicle. Poikilocapnic and isocapnic hypoxic ventilatory responsiveness were similar among treatments. One minute after reoxygenation, animals given Acz exhibited posthypoxic frequency decline, a lower coefficient of variability for frequency, and no tendency toward periodic breathing, compared with vehicle treatment. We conclude that Acz improves unstable breathing in the B6 model, without altering hypoxic response or producing short-term potentiation, but with some blunting of hypercapnic responsiveness.     

Diphasic ventilatory response to hypoxia in newborn lambs

The ventilatory response of newborn lambs to hypoxemia was evaluated in two groups of seven awake lambs studied at 2 and 7 days of life. Minute ventilation (VE) and airway occlusion pressure (P0.1) were monitored as the animals were exposed in sequence to room air, 12% O2 (15 min), 7% O2 (15 min), and room air. On 12 and 7% O2, 2-day-old lambs experienced a brisk hyperventilation followed by a VE depression, previously described in newborns of other species (diphasic response). The 7-day-old lambs had a clear diphasic VE response only on 7% O2 breathing. In the 2-day-old lambs, at the time of the relative VE depression to 12% O2, the respiratory centers showed a persisting responsiveness to further hypoxia; switching to 7% O2 caused a brisk increase in VE and P0.1 of 70 and 130%, respectively, which was followed again by a VE depression. The magnitude of the immediate VE response to hypoxia, taken as an index of the chemoreceptor strength, was inversely related to the magnitude of the VE depression (R = 0.81, P less than 0.001). It was concluded that 1) lambs as well as other neonates have an age-related diphasic VE response to hypoxia; 2) at the time of the VE depression, the respiratory centers maintain their responsiveness to further acute hypoxia; and 3) the weakness of the chemoreceptors in the newborn is a major determinant of the diphasic response.     

Ventilatory effects of substance P-saporin lesions in the nucleus tractus solitarii of chronically hypoxic rats

During ventilatory acclimatization to hypoxia (VAH), time-dependent increases in ventilation lower Pco(2) levels, and this persists on return to normoxia. We hypothesized that plasticity in the caudal nucleus tractus solitarii (NTS) contributes to VAH, as the NTS receives the first synapse from the carotid body chemoreceptor afferents and also contains CO(2)-sensitive neurons. We lesioned cells in the caudal NTS containing the neurokinin-1 receptor by microinjecting the neurotoxin saporin conjugated to substance P and measured ventilatory responses in awake, unrestrained rats 18 days later. Lesions did not affect hypoxic or hypercapnic ventilatory responses in normoxic control rats, in contrast to published reports for similar lesions in other central chemosensitive areas. Also, lesions did not affect the hypercapnic ventilatory response in chronically hypoxic rats (inspired Po(2) = 90 Torr for 7 days). These results suggest functional differences between central chemoreceptor sites. However, lesions significantly increased ventilation in normoxia or acute hypoxia in chronically hypoxic rats. Hence, chronic hypoxia increases an inhibitory effect of neurokinin-1 receptor neurons in the NTS on ventilatory drive, indicating that these neurons contribute to plasticity during chronic hypoxia, although such plasticity does not explain VAH.     

Respiratory stimulation by female hormones in awake male rats.

The respiratory effect of progestin differs among various animal species and humans. The rat does not hyperventilate in response to exogenous progestin. The present study was conducted to determine whether administration of combined progestin and estrogen prompts ventilatory stimulation in the male rat. Ventilation, blood gases, and metabolic rates (O2 consumption and CO2 production) were measured in the awake and unrestrained male Wistar rat. The combined administration of a synthetic potent progestin (TZP4238) and estradiol for 5 days significantly increased tidal volume and minute expiratory ventilation (VE), reduced arterial PCO2, and enhanced the ventilatory response to CO2 inhalation (delta VE/delta PCO2). On the other hand, respiratory frequency, O2 consumption, CO2 production, and body temperature were not affected. The arterial pH increased slightly, with a concomitant decrease in plasma [HCO3-]. Administration of either TZP4238 or estradiol alone or vehicle (Tween 80) had no effect on respiration, blood gases, and ventilatory response to CO2. The results indicated that respiratory stimulation following combined progestin plus estradiol treatment in the male rat involves activation of process(es) that regulate tidal volume and its augmentation during CO2 stimulus.     

Influences of gender and sex hormones on hypoxic ventilatory response in cats.

Hypoxic ventilatory response (HVR) is known to be increased by female as well as male sex hormones, but whether there are differences in HVR between men and women remains unclear. To determine whether gender differences exist in HVR, we undertook systematic comparisons of resting ventilation and HVR in awake male and female cats. Furthermore to explore the potential contribution of sex hormones to gender differences observed, we compared neutered and intact cats of both sexes. Resting ventilation differed among the four groups, but differences disappeared with correction for body weight. Intact females had a lower end-tidal PCO2 than intact male cats (females: 31.6 +/- 0.4 Torr vs. males: 33.6 +/- 0.4 Torr, P less than 0.05), indicating an increased alveolar ventilation per unit CO2 production. HVR expressed as the shape parameter A was similar among the four groups of animals. However, baseline (hyperoxic; end-tidal PO2 greater than 200 Torr) minute ventilation [VI(PO2 greater than 200)] differed among the groups. Therefore we normalized HVR by dividing the shape parameter A by VI(PO2 greater than 200) to compare the relative hypoxic chemosensitivity among the various groups of animals. In addition, we further normalized HVR for body weight, because body size influences ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal sex steroids affect ventilatory responses to aspartic acid and NMDA receptor subunit 1 in rats.

We hypothesized that administration of estradiol benzoate to males and testosterone propionate to female neonatal rat pups alters sex-specific ventilatory responses to aspartic acid with correspondent changes in N-methyl-D-aspartate receptor subunit 1 (NR1) expression determined by Western blot in specific brain regions. One-day-old rat pups received estradiol benzoate, testosterone propionate, or vehicle and were studied at weanling and adulthood. Different groups had distinct patterns of changes in tidal volume and frequency of breathing after aspartic acid administration. NR1 expression in hypothalamus was altered by age, sex, and treatment. Medullary and pontine NR1 expression correlated with baseline ventilation and magnitude of the ventilatory response to aspartic acid in some groups. Thus 1) tidal volume and breathing frequency patterns in response to aspartic acid are gender, age, and treatment dependent; 2) sex, age, and exogenous steroid hormones affect NR1 expression primarily in the hypothalamus; and 3) there is correlation between NR1 expression in pons and medulla with ventilatory parameters.     

Gender-specific effects of thyroid hormones on cardiopulmonary function in SHHF rats.

Spontaneously hypertensive heart failure (SHHF) rats develop hypertension and heart failure. We hypothesized that induction of hyperthyroidism should accelerate development of heart failure in male SHHF rats. Male and female SHHF rats received diets containing desiccated thyroid glands (DTG) or a control diet for 8 wk. Male and female Wistar-Kyoto rats were used as normotensive controls. DTG treatment reduced body weight in male, but not female, SHHF rats but increased body temperature and heart weight-to-body weight ratio in both genders. In DTG-treated male SHHF rats, serum triiodothyronine levels doubled relative to SHHF controls, whereas O2 consumption increased in DTG-treated SHHF rats. Frequency of breathing in air increased in DTG-treated female rats, and ventilation increased in DTG-treated male rats. Ventilatory equivalents exhibited gender differences in SHHF rats, were decreased in both genders by DTG treatment, and reached levels similar to those of Wistar-Kyoto rats. DTG increased heart rate, right ventricular pressure, and contractility in both genders and increased left ventricular pressure in SHHF male rats. These results refute our hypothesis and suggest that cardiopulmonary function of SHHF male rats may be improved by DTG treatment.     

Norepinephrine turnover in the rat pineal gland. Acceleration by estradiol and testosterone.

The administration of 0.5 mg of testosterone propionate (TP) to orchiectomized rats or of 2 ug of estradiol to oophorectomized rats resulted in significantly less ³H-norepinephrine remaining in the pineal gland 60 and 120 min after a pulse injection of the radioactive compound. This effect was not observed in animals administered with ³H-norepinephrine 45 or 180 min after a single hormone injection. Half-lives for ³H-norepinephrine disappearance in estradiol- and TP-treated rats were 62 and 60 min respectively whereas those of female and male vehicle-injected controls were 109 and 123 min respectively. Hormone treatment did not affect pinela norepinephrine content in any of the schedules used. Norepinephrine efflux expressed as pg. mg tissue⁻¹. min⁻¹ was 33 in estradiol-treated females, 17 in vehicle-treated females, 28 in TP-treated males and 12 in vehicle-treated males. These data indicate that the norepinephrine turnover in neurons innervating the pineal gland is increased by chronic administration of female and male sex hormones.