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S F Leibowitz

Publications and source records attributed to S F Leibowitz.

At least 55 records · Page 3Linked to original sources
PubMed1993

Effects of serotonin and the serotonin blocker metergoline on meal patterns and macronutrient selection.

Serotonin [5-hydroxytryptamine(5-HT)] in the paraventricular nucleus (PVN) of rats has a suppressive effect on feeding behavior and causes a selective decrease in carbohydrate ingestion, specifically at the onset of the natural (dark) feeding period. Studies conducted here provide further evidence for this phenomena, showing a similar dose-related decrease in carbohydrate ingestion at dark onset after PVN injection of 5-HT or of the agonists, d-norfenfluramine or fluoxetine, which act through endogenous 5-HT. To further characterize the effects of this indoleamine on the macrostructure of feeding, a computer-automated data acquisition system was used to analyze macronutrient feeding patterns in freely feeding animals maintained on the pure diets of protein, carbohydrate, and fat. Results indicate that PVN administration of 5-HT at dark onset decreases intake of the carbohydrate nutrient by decreasing meal size, feeding time, and feeding rate for this nutrient and increasing the satiating effect of carbohydrate. These effects, which occur specifically during the first meal after injection, are opposite those seen after peripheral administration of the 5-HT receptor antagonist, metergoline. This drug stimulates feeding through a selective increase in carbohydrate intake, characterized by an increase in meal size, percent composition, and feeding time for this nutrient and a decrease in the satiety ratio for carbohydrate. These results implicate the serotonergic system in the termination of carbohydrate-rich meals that are prevalent during the early hours of the natural feeding cycle.

Animals↗
PubMed1993

Changes in extracellular PVN monoamines and macronutrient intake after idazoxan or fluoxetine injection.

Norepinephrine (NE) and serotonin (5-HT) in the paraventricular nucleus (PVN) have opposite effects on feeding, with NE stimulating carbohydrate intake through alpha 2 noradrenergic receptors and 5-HT inhibiting carbohydrate intake. This study examined the action of drugs that affect brain monoaminergic systems, in terms of their impact on nutrient intake and on PVN monoamines measured using microdialysis. The drugs studied were idazoxan, a blocker of alpha 2 receptors, or fluoxetine, a 5-HT reuptake blocker. In rats maintained on pure macronutrient diets, idazoxan (1 mg/kg) and fluoxetine (10 mg/kg), 120 min after injection both reduced total food intake, and specifically carbohydrate intake. In dialysis experiments, successive 20-min dialysate samples were taken, three samples before and seven samples after intraperitoneal injection of idazoxan (5 and 20 mg/kg), fluoxetine (10 mg/kg), or vehicle. Idazoxan increased NE, homovanillic acid, and dihydroxyphenylacetic acid in the PVN. Fluoxetine induced a significant increment of 5-HT in PVN, while producing a smaller increase in NE, dopamine, and homovanillic acid. These results support the conclusion that the impact of these drugs on macronutrient intake may be a consequence of their action on endogenous monoamine systems in the PVN. Thus, in this nucleus, the blockade of alpha 2-noradrenergic receptors, like stimulation of 5-HT receptors, attenuates normal ingestion of carbohydrate.

Adrenergic alpha-Antagonists↗
PubMed1993

Effect of paraventricular injection of neuropeptide Y on milk and water intake of preweanling rats.

This study investigated the effect of paraventricular nucleus (PVN) injection of neuropeptide Y (NPY) on milk and water intake of 2- and 15-day-old sated rats. On the day prior to testing, rat pups were removed from their mothers and implanted with a cannula directed unilaterally at the PVN. On the following day, each pup was implanted with an intra-oral cannula for oral infusion of milk or water that could be swallowed or rejected. Following a 1-hour period fo satiation, each pup received a PVN injection of saline or a single dose of NPY (23.5-235.0 pmol). Milk or water intake was then assessed in a 1-hour test period. Injection of NPY into the PVN enhanced milk and water intake equally at 2 days of age. At 15 days, NPY produced a significantly greater enhancement of milk than water intake. These findings, which are similar to those observed previously with PVN injections of norepinephrine (NE), suggest that: (1) NPY receptors in the PVN, like alpha 2-noradrenergic receptors, are functional very early in the postnatal development of the rat; (2) NPY, in addition to its orexigenic effect, produces a small but significant dipsogenic effect; and (3) NPY may function cooperatively with NE in the PVN to stimulate feeding and drinking beginning at a very early age.

Animals↗
PubMed1993

Glucocorticoid receptors in PVN: interactions with NE, NPY, and Gal in relation to feeding.

Norepinephrine (NE) and neuropeptide Y (NPY) potentiate carbohydrate ingestion after injection into the paraventricular nucleus (PVN), whereas injection of galanin (Gal) potentiates fat intake. The present study examines the relation between these neurochemically induced feeding behaviors and the adrenal steroids acting locally within the PVN. Results demonstrate that PVN NE- and NPY-induced carbohydrate intake is abolished by adrenalectomy surgery (ADX) and by local PVN implants of the type II receptor antagonist RU-486. Carbohydrate intake in response to PVN NE or NPY injection is unaffected by the type I antagonist RU-28318. In contrast, the stimulatory effect of PVN Gal injection on fat intake is unchanged by surgical ADX or by PVN administration of RU-486 or RU-28318, suggesting that the stimulatory action of Gal on fat ingestion occurs independently of corticosterone (Cort) and of PVN type I or type II steroid receptors. It is concluded that endogenous Cort has a permissive effect on the carbohydrate feeding responses elicited by NE and NPY in the PVN and that this interaction is mediated by type II glucocorticoid receptors within this nucleus.

Adrenalectomy↗
PubMed1993

Adrenal steroid receptors in the PVN: studies with steroid antagonists in relation to macronutrient intake.

These studies tested the impact of steroid receptor antagonists on food intake induced by steroid agonists implanted into the paraventricular nucleus (PVN) and also on feeding that naturally occurs at the onset of the active (dark) period in the rat. Implants of corticosterone (CORT) or the selective type II agonist RU28362 in the PVN stimulated feeding in adrenalectomized (ADX) rats, specifically by enhancing carbohydrate ingestion. This feeding response induced by CORT or RU28362 was blocked by PVN implants of the type II antagonist RU486 but was unaffected by the type I antagonist RU28318. In contrast, the type I agonist aldosterone (ALDO) in the PVN stimulated feeding in both sham and ADX rats by preferentially enhancing fat ingestion, which could be inhibited by the type I antagonist RU28318 but not by the type II antagonist RU486. These results indicate that the feeding elicited by CORT at dark onset is dependent upon the functional integrity of type II glucocorticoid receptors within the PVN, in contrast to the feeding elicited by ALDO which is dependent upon endogenous type I steroid receptor activation within this nucleus. Test results with these antagonists alone in freely feeding animals support a functional role for these PVN steroid receptors in adrenal steroid control of natural food intake. Specifically, blockade of PVN type II receptors with RU486 in intact rats selectively suppressed spontaneous carbohydrate feeding at dark onset, while PVN implants of the type I receptor antagonist RU28318 caused a suppression of spontaneous fat intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1992

Impact of a galanin antagonist on exogenous galanin and natural patterns of fat ingestion.

The peptide galanin (GAL) has a potent stimulatory effect on fat ingestion after administration into the hypothalamic paraventricular nucleus (PVN). This study examined a newly synthesized GAL antagonist, M40, in two separate experiments involving: (1) PVN injections of M40 alone in freely feeding animals, to investigate the importance of endogenous GAL receptor activity in determining natural patterns of fat ingestion, and (2) PVN injections of M40 in combination with exogenous GAL, to determine whether endogenous GAL receptors mediate this peptide-induced response. The results demonstrate that PVN injection of M40 by itself dose-dependently (2-108 pmol) reduces spontaneous ingestion of the fat diet. This phenomenon is robust, behaviorally specific and opposite to that induced by GAL itself. Moreover, the stimulatory effect of PVN-injected GAL on fat ingestion can be blocked by prior PVN administration of M40 at relatively low doses (2-6 pmol), indicating that M40 is a potent antagonist of GAL receptors in the hypothalamus. Together, these results provide the first evidence for the existence of endogenous GAL receptors in mediating the action of exogenous GAL in the hypothalamus. They also constitute a crucial step in demonstrating a physiological function of these PVN GAL receptors in controlling natural patterns of fat ingestion.

Animals↗
PubMed1992

The pharmaco-ontogeny of the perifornical lateral hypothalamic beta 2-adrenergic and dopaminergic receptor systems mediating epinephrine- and dopamine-induced suppression of feeding in the rat.

The functional ontogeny of beta 2-adrenergic and dopaminergic receptors in the perifornical lateral hypothalamus (PLH) that mediate adrenergic and dopaminergic suppression of feeding in rats was investigated. Rat pups, ranging in age from 2 to 15 days, were removed from their mothers and implanted with a brain cannula directed unilaterally at the PLH or a more rostral site lateral to the anterior nucleus of the hypothalamus. On the next day, following a 22-h period of food and water deprivation, each pup was implanted with an intra-oral cannula for oral infusion of milk that could be swallowed or rejected. Subsequently, each pup received an intracerebral injection of saline, or a single dose of epinephrine (EPI, 0.1-30.0 nmol), the beta 2-adrenergic receptor agonist salbutamol (1.0-30.0 nmol) or the dopaminergic receptor agonist apomorphine (1.0-30.0 nmol). Milk intake was then assessed following a 1-h period of infusion. The results showed significant dose-dependent suppression of milk intake in pups as young as 2 days of age in response to PLH injection of EPI, salbutamol and apomorphine. In contrast to its effectiveness in the PLH at 2 days of age, EPI failed to suppress milk intake at this age following injection into a more rostral site lateral to the anterior nucleus of the hypothalamus. Together, these findings suggest that both beta 2-adrenergic and dopaminergic receptors, mediating adrenergic and dopaminergic suppression of feeding, are functionally mature very early in the postnatal development of the rat. Moreover, consistent with evidence in adult rats, these catecholaminergic receptors in young pups appear to be located in the region of the PLH.

Aging↗
PubMed1992

The pharmaco-ontogeny of the paraventricular alpha 2-noradrenergic receptor system mediating norepinephrine-induced feeding in the rat.

The present study was undertaken to assess the functional ontogeny of alpha 2-noradrenergic receptors in the hypothalamic paraventricular nucleus (PVN) that mediate noradrenergic stimulation of feeding in the rat. Rat pups, ranging in age from 2 to 15 days, were removed from their mothers and implanted with a brain cannula directed unilaterally at the PVN or third ventricle. On the following day, each pup was implanted with an intra-oral cannula for oral infusion of milk or water that could be swallowed or rejected. Following a 1-h period of satiation, each pup received an intracerebral injection of saline, or a single dose of norepinephrine (NE, 0.01-100.0 nmol) or the alpha 2-noradrenergic receptor agonist clonidine (0.01-1.0 nmol). Milk or water intake was then assessed following a 1-h period of infusion. Injection of NE into the PVN and third ventricle significantly enhanced milk intake at 2 days of age. NE was 10-fold more potent in the PVN than in the ventricle. While paraventricular injections of NE stimulated milk and water intake equally at 2 days of age, NE produced a greater stimulation of milk than water intake at 15 days of age. Like NE, clonidine significantly enhanced milk intake at 2 days of age following injection into the PVN. Collectively, these findings suggest that alpha 2-noradrenergic receptors, mediating noradrenergic stimulation of feeding, are functionally mature very early in the postnatal development of the rat. Moreover, consistent with evidence in the adult rat, these findings indicate that alpha 2-noradrenergic receptors relevant to feeding are located in the vicinity of the PVN.

Animals↗
PubMed1992

Differential effects of galanin and neuropeptide Y on extracellular norepinephrine levels in the paraventricular hypothalamic nucleus of the rat: a microdialysis study.

Evidence suggests that the peptides galanin (GAL) and neuropeptide Y (NPY) interact with the amine norepinephrine (NE) in the hypothalamic paraventricular nucleus (PVN) to stimulate feeding behavior. To directly investigate the nature of these interactions, extracellular levels of PVN NE were monitored in freely-moving rats using the microdialysis/HPLC technique. Following PVN administration of GAL (0.3 nmol), NPY (78 pmol) or Ringer's solution, local NE levels were measured at 20-min intervals for 2 hrs postinjection, under two feeding conditions, namely, in the presence or absence of food. The results demonstrate different effects of these peptides on endogenous NE levels. Following GAL administration, PVN NE levels were enhanced by 80 to 90%, up to 40 min postinjection, independent of food availability. In contrast, following NPY injection, NE levels were significantly reduced 20 min postinjection with food absent, and when food was available, NE levels tended to be enhanced. These results, consistent with pharmacological and biochemical studies, reveal different patterns of peptide-amine interactions in the PVN.

Animals↗
PubMed1992

Effects of adrenal steroid agonists on food intake and macronutrient selection.

These experiments tested the effects of subcutaneous (SC) and paraventricular nucleus (PVN) administration of the steroid receptor agonists, corticosterone (CORT), aldosterone (ALDO), RU28362, and dexamethasone (DEX), on food intake and macronutrient selection during the first h of the dark feeding period in the rat. Results indicate that CORT and the selective type II receptor agonist RU28362 specifically stimulate carbohydrate ingestion after SC or PVN administration, while DEX has no effect on feeding. This selective effect of SC CORT on carbohydrate ingestion is dose dependent, seen at doses ranging from 0.125 to 2.0 mg/kg. Moreover, the stimulatory effects of CORT and RU28362 on carbohydrate intake are observed in ADX rats but not in sham rats. This is in contrast to SC and PVN administration of the type I receptor agonist ALDO, which specifically enhances fat ingestion in both sham and ADX rats. These results, with both peripheral and central steroid administration, reveal selective effects of type I and type II receptor stimulation on fat and carbohydrate intake, respectively.

Adrenalectomy↗
PubMed1992

Effect of food deprivation and refeeding on the concentration of vasopressin and oxytocin in discrete hypothalamic sites.

Recent evidence has implicated hypothalamic peptides, such as arginine vasopressin (AVP) and oxytocin (OT) in the control of feeding behavior. In this study, we investigated the impact of food deprivation (48 h) and subsequent refeeding (6 h) on the concentration of AVP and OT in discrete hypothalamic areas, as well as in the neurohypophysis. We also estimated in these rats certain peripheral measures, including hydroelectrolytic parameters, plasma and urine AVP, and plasma corticosterone. The results of this study revealed that food deprivation for 48 h produced little change in OT concentration in the various hypothalamic nuclei studied, including the paraventricular and supraoptic nuclei, with the exception of the median eminence (ME), where a significant decline (-36%; p < 0.05) was detected. This effect was not significantly reversed by 6 h of refeeding. With respect to AVP concentration, food deprivation caused a reliable decline exclusively in the parvocellular subdivision of the paraventricular nucleus (pPVN; -45%; p < 0.01) and in the supraoptic nucleus (SON; -45%; p < 0.01). No change in AVP was detected in the ME or in most other hypothalamic nuclei examined. Refeeding for 6 h actually potentiated the effect of food deprivation, decreasing further from baseline the content of AVP in the pPVN and SON. The only other hypothalamic area to exhibit a change in AVP content was the ventromedial nucleus, where AVP level increased (p < 0.001) after deprivation and declined to normal after 6 h of refeeding. The content of AVP and OT in the neurohypophysis was unaffected by food deprivation and subsequent refeeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Neurochemical-neuroendocrine systems in the brain controlling macronutrient intake and metabolism.

Appetite, energy balance and body weight gain are modulated by diverse neurochemical and neuroendocrine signals from different organs in the body and diverse regions in the brain. The hypothalamus plays an important integrative function in this process, acting through a variety of systems that involve a close interaction between nutrients, amines, neuropeptides and hormones. These systems underlie normal nutrient intake and metabolism and are thought to be responsible for shifts in feeding behavior across the circadian cycle and fluctuations relating to gender and age in both rats and humans. Moreover, alterations in these normal neurochemical-neuroendocrine systems may be associated with abnormal eating patterns, such as anorexia nervosa, bulimia and obesity. Understanding the systems that control eating behavior might provide a foundation for the treatment and possible prevention of such disorders.

Animals↗
PubMed1992

Blockade of natural and neuropeptide Y-induced carbohydrate feeding by a receptor antagonist PYX-2.

Neuropeptide Y (NPY injected into the paraventricular nucleus (PVN) of rats has a potent stimulatory effect specifically on carbohydrate intake. This study examined the behavioral effects of a newly synthesized NPY antagonist, PYX-2. After PVN injection of PYX-2 (50-900 pmoles) alone, a strong dose-dependent reduction in spontaneous carbohydrate intake at the onset of the dark cycle was observed in freely-feeding rats. Moreover, at even lower doses (12.5 and 25.0 pmoles), PYX-2 also blocked the stimulatory action of PVN NPY (100 pmoles) on carbohydrate ingestion. These results provide the first evidence for the existence of endogenous NPY receptors in mediating the action of exogenous NPY in the hypothalamus. They also constitute a crucial step in demonstrating a physiological function of these PVN NPY receptors specifically in controlling carbohydrate ingestion at the onset of the natural feeding cycle.

Anesthesia↗
PubMed1991

Effect of hypothalamic and peripheral fluoxetine injection on natural patterns of macronutrient intake in the rat.

The effect of the serotonin (5-HT) reuptake inhibitor, fluoxetine (FLU), on nutrient intake was examined in rats given free access to three pure macronutrient diets (protein, carbohydrate and fat). Fluoxetine was administered either peripherally or directly into the hypothalamic paraventricular nucleus (PVN) at three different times of the rats' nocturnal cycle. Using a range of doses for IP (0.6-10 mg/kg) and PVN injection (3.2-100 nmol), FLU exerted a selective, dose-dependent suppression (-20% to -60%) of carbohydrate intake only during the first hour of the dark. No change in the consumption of protein or fat was observed. This suppressive effect in the early dark period was not observed during the late dark phase, after either IP or PVN administration. In animals with brain cannulae aimed at different hypothalamic nuclei, the nutrient-suppressive effect of FLU was found to be localized to the medial hypothalamic nuclei, namely, the ventromedial, dorsomedial and suprachiasmatic nuclei, in addition to the PVN. These results, along with other published work, support a role for hypothalamic 5-HT systems in the control of nutrient intake in a circadian-related manner and in mediating the central action of the anorectic compound FLU.

Analysis of Variance↗
PubMed1991

Developmental patterns of macronutrient intake in female and male rats from weaning to maturity.

Male and female Sprague-Dawley rats had available pure macronutrient diets, protein, carbohydrate and fat, from birth to day 77 of age. Analyses of their intake of these nutrients, as a function of age, demonstrate that, in both sexes, daily protein intake and preference for this nutrient relative to the other macronutrients rise steadily from weaning and peak precisely at the time of puberty (day 37-44 for females and days 42-49 for males), when there is also a peak in body weight gain. This is in contrast to daily carbohydrate intake, which peaks 2 weeks after puberty in males, and also to the female and male rats' preference for carbohydrate, which remains relatively stable from weaning to maturity. These patterns also differ from those observed for daily fat intake and fat preference for females and males, which are relatively high during the first postweaning week and then decline and remain very low until shortly after puberty (day 54), when there occurs a sharp burst in fat intake. Comparisons between the females and males reveal a significantly stronger preference for carbohydrate in the females, exhibited as early as 23 days of age; a stronger preference for protein and fat in the males, evident after day 28; and greater light-period feeding of carbohydrate and fat by females compared to males, apparent after puberty. Correlational analyses demonstrate that body weight and total kcal intake are closely related to daily protein consumption, more strongly in females compared to males; are strongly related to daily fat intake only in males; and are unrelated to intake of carbohydrate, at any age and in either sex.

Aging↗
PubMed1991

Self-selecting albino rats exhibit differential preferences for pure macronutrient diets: characterization of three subpopulations.

Analyses of natural feeding behavior in albino male Sprague-Dawley rats demonstrate that, when allowed to self-select from pure macronutrient diets (protein, carbohydrate and fat), these rats of the same genetic strain can be categorized into 3 subpopulations according to either their 24-h or their 12-h nocturnal patterns of nutrient intake. A majority of the animals (HC for high carbohydrate, 50% of the total population) consumed a diet rich in carbohydrate relative to protein or fat, while a smaller population of rats (HF, 30%) preferred the fat diet, and an even smaller population (HP, 20%) chose a high-protein diet. These 3 subpopulations, after a few weeks of maintenance on the diets, differed in their body weight, with the HF rats having a higher body weight than the HP animals, who tended to weigh more than the lightest HC rats. Whereas all subgroups exhibited a similar bimodal distribution of feeding during the nocturnal cycle, with peaks during the early and late dark periods, they were distinguishable on the basis of their nutrient consumption during specific phases of the dark cycle. This difference was most apparent in the early dark phase, when the 3 subgroups exhibited exaggerated preferences for the specific nutrient that was generally preferred over the 24-h cycle. This is in contrast to the middle dark phase, when diet preferences were attenuated or lost, and the late dark phase, when most rats were similar in showing an increased preference for protein and fat and a decreased preference for carbohydrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Higher alpha-noradrenergic receptors in paraventricular nucleus of obese Zucker rats: decline after food deprivation.

Norepinephrine (NE), acting through alpha 2-noradrenergic receptors in the hypothalamic paraventricular nucleus (PVN), has been implicated in the control of feeding behavior and body weight gain. To determine whether this hypothalamic receptor system is disturbed in genetically obese rats, the binding of radioligands to alpha 2-noradrenergic, as well as to alpha 1-noradrenergic, receptors was examined in seven hypothalamic nuclei of obese Zucker rats relative to their lean littermates. Receptor binding procedures, using the alpha 2-noradrenergic agonist [3H]p-aminoclonidine ([3H]PAC) and the alpha 1-noradrenergic antagonist [3H]prazosin, demonstrated that the obese rats, compared to the lean rats, had significantly greater alpha 2-noradrenergic and alpha 1-noradrenergic receptor binding, specifically in the PVN as opposed to other hypothalamic areas examined. Moreover, the obese rats, compared to the lean rats, exhibited greater responsiveness to the effects of food deprivation (48 h), which caused a significant decline in radioligand binding to both alpha 2 and alpha 1 receptors, specifically in the PVN. A decrease in alpha 2-receptor binding after deprivation in the obese rats was also seen in two basal hypothalamic areas, namely, the supraoptic nucleus and arcuate nucleus-median eminence. The possibility exists that these disturbances in hypothalamic alpha-receptors may be involved in the development and/or maintenance of the genetic obesity.

Adrenergic alpha-Agonists↗