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Biomedical subjects

S F Leibowitz

Publications and source records attributed to S F Leibowitz.

At least 73 records · Page 4Linked to original sources
PubMed1991

Effects of adrenalectomy on macronutrient selection patterns in the rat.

The present studies examined the effects of adrenalectomy (ADX) on nutrient selection of rats over the 24-h period, as well as during the first 2 h of the nocturnal feeding cycle. Results indicate that ADX, in rats showing generally similar preferences for carbohydrate and fat, equally suppresses intake of both of these nutrients over the 24-h period. The relative impact of ADX on carbohydrate and fat intake may shift depending upon baseline, with carbohydrate-preferring rats showing a stronger decrease in intake of this diet after ADX and fat-preferring rats exhibiting a greater decline in fat intake after ADX. Acute injections of corticosterone (CORT) and aldosterone (ALDO) are both found to restore carbohydrate as well as fat intake to ADX rats over the 24-h period. However, in the first 2 h of the dark feeding cycle, carbohydrate intake is found to be selectively suppressed after ADX, and CORT injection (0.5 and 2.0 mg/kg, SC) restores carbohydrate intake during this early dark period, while producing a small increase in fat intake only at the higher dose. This is in contrast to ALDO administration at dark onset, which has a stronger stimulatory effect on fat intake in the ADX rat but does not fully restore carbohydrate intake. These findings indicate that CORT and ALDO have differential effects on nutrient intake in ADX rats particularly at the onset of the dark cycle, and it is suggested that these effects are mediated, respectively, by the type I and type II steroid receptor systems in the brain.

Adrenal Glands↗
PubMed1990

Diurnal rhythm of neuropeptide Y-like immunoreactivity in the suprachiasmatic, arcuate and paraventricular nuclei and other hypothalamic sites.

The diurnal rhythm of neuropeptide Y (NPY)-like immunoreactivity was examined in 9 discrete hypothalamic sites of rats maintained on a 12:12 h light/dark cycle. Significant bimodal rhythms of NPY concentration were detected in the suprachiasmatic and arcuate nuclei, with significant peaks just prior to onset of the nocturnal period and also at onset of the light period. In the parvocellular division of the paraventricular nucleus, a unimodal NPY peak was observed prior to dark onset. No diurnal rhythm was seen in the magnocellular division of the paraventricular nucleus, nor in 5 other hypothalamic areas examined.

Animals↗
PubMed1990

Galanin inhibits insulin and corticosterone release after injection into the PVN.

The neuropeptide galanin (GAL, 1 microgram/0.3 microliters) was injected into the paraventricular nucleus (PVN) at two different times of the 12:12 h light/dark cycle, namely 2 h before the dark ('pre-dark') and before the light ('pre-light') periods. Blood samples were collected 15 min after injection and examined for serum levels of insulin (INS), corticosterone (CORT) and glucose (GLUC). Results indicate that PVN GAL injection in the pre-dark period strongly inhibits both CORT and INS release but has no effect on GLUC levels. These hormone changes, however, were not detected in the blood samples collected in the pre-light period. At this time, baseline levels of CORT were significantly lower than in the pre-dark period, while INS and GLUC levels were generally similar at both time periods. These results indicate that the effects of PVN GAL on CORT and INS secretion are inhibitory in nature and are temporally linked to the diurnal cycle.

Animals↗
PubMed1990

Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status.

Neuropeptide Y (NPY) is believed to regulate the normal eating behavior and body weight in rats via central mechanisms. We have investigated whether NPY, which stimulates food intake, may in turn be modified by the nutritional state of the animals. Thus the impact of food deprivation (FD) (48 h) and subsequent refeeding on the levels of NPY in discrete hypothalamic areas was examined in this study. The results showed site specific change in only 3 of 7 hypothalamic sites. A 5-fold increment in NPY was reported in the paraventricular nucleus (PVN) and a 10-fold increase was observed in the arcuate nucleus-median eminence (ARC-ME). While subsequent refeeding for 6 h reversed the effect of FD in the ARC-ME, the levels of NPY in the PVN remained high in the refed rats. The perifornical lateral hypothalamus displayed a different pattern, namely, a significant increase in NPY content in refed as compared to satiated and deprived rats. The NPY levels in 4 other hypothalamic sites, namely, the dorsomedian, ventromedian, supraoptic and suprachiasmatic nuclei, and two extrahypothalamic sites, namely caudate nucleus and nucleus accumbens, showed total resistance to any change following deprivation and refeeding. These data emphasize the important and specific role of the paraventricular and arcuate nuclei in NPY's regulation of food intake and provide support for the idea that the variations of hypothalamic NPY after food deprivation reflect a specific physiological response of feeding regulatory system to alterations in the animal nutritional state and body weight.

Animals↗
PubMed1990

Peptide-amine interactions in the hypothalamic paraventricular nucleus: analysis of galanin and neuropeptide Y in relation to feeding.

The neuropeptide galanin (GAL) has been found to elicit feeding after injection into the paraventricular hypothalamic nucleus (PVN), where it coexists with norepinephrine (NE), a neurotransmitter believed to be important in the control of natural feeding behavior. Using pharmacological tools, this study investigated the possibility that PVN GAL influences food intake via its direct interaction with the noradrenergic system localized in this nucleus. Tests with alpha-adrenergic receptor blockers demonstrated that GAL-induced feeding, similar to NE-stimulated feeding, depends specifically upon functional alpha 2-receptor sites. Further, experimentation with the catecholamine synthesis inhibitors, alpha-methyl-p-tyrosine and Fla-63, suggested that GAL's action also depends upon the release of endogenous NE. This is in contrast to another hypothalamic peptide, neuropeptide Y, which is also a strong stimulant of food intake and coexists with NE in the PVN. Neuropeptide Y remains effective in eliciting feeding in the presence of alpha 2-receptor antagonists and catecholamine-synthesis inhibitors, suggesting that, unlike GAL, it can act independently of endogenous NE.

Adrenergic alpha-Antagonists↗
PubMed1990

Metabolic effects of neuropeptide Y injections into the paraventricular nucleus of the hypothalamus.

The metabolic effects of single injections of neuropeptide Y (NPY) into the paraventricular hypothalamus were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. Over the dose range of 10-156 pmol NPY had large effects on respiratory quotient (RQ) while having no effect on energy expenditure or locomotor activity. The effects of NPY on RQ were unusual both in respect to their dose-response and time-dose-response characteristics. The lowest dose (10 pmol) produced a very low latency reduction in RQ which indicates a decreased utilization of carbohydrates as an energy substrate. The next higher dose (20 pmol) had no effect, whereas the next three doses (39, 78 and 156 pmol) produced increases in RQ which indicate an increased utilization of carbohydrates as an energy substrate. Surprisingly, the latencies of the increased RQs were dose-dependent over the range of 30 min to 20 h with the highest dose producing the longest latency effect. The finding of a positive relation of dose to response latency over a time range of from a few minutes to 20 h is unprecedented and appears to represent a neuromodulatory effect of NPY that acts in concert with its neurotransmitter effects. These data highlight the central role of NPY in modulating energy substrate utilization and indicate the importance of elucidating time-dose-response relationships when investigating the effects of NPY.

Animals↗
PubMed1990

Mapping study of noradrenergic stimulation of vasopressin release.

The precise role of hypothalamic norepinephrine (NE) in the control of vasopressin (AVP) release has remained unclear, due to reports of both inhibitory and excitatory effects of NE and only a few studies with direct hypothalamic manipulations. The present study utilized a chronically implanted swivel brain cannula to investigate, in undisturbed and freely behaving rats, the impact of acute hypothalamic infusions of monoamines on circulating AVP levels. The first study examined and compared the responsiveness of six hypothalamic sites to NE infusion through the swivel cannula. Results indicated that the excitatory effect of central noradrenergic stimulation on serum AVP is highly site specific, localized to the paraventricular (PVN) and supraoptic (SON) nuclei. These two nuclei appeared to be equally responsive to NE infusion, yielding a threefold rise in serum AVP over baseline levels. In contrast, NE in the dorsomedial nucleus produced a significantly smaller increase in AVP, and no response was observed in the ventromedial nucleus, posterior hypothalamus, or perifornical lateral hypothalamus. Further tests conducted in the PVN showed this nucleus to respond in a dose-dependent manner to NE infusion. In contrast, under similar test conditions, dopamine caused only a small increase in AVP at a relatively high dose, while a PVN injection of serotonin produced no response. These results support the existence of an excitatory noradrenergic system controlling AVP release and specifically demonstrate that this function of NE is localized to the PVN and SON, in contrast to other hypothalamic areas, and is mimicked to some extent by dopamine but not by serotonin.

Animals↗
PubMed1990

The ontogeny of opioid receptors mediating opiate-induced feeding in rats.

Acute administration of naloxone to preweanling rats does not attenuate independent ingestion of milk until 14 days of age suggesting that the full expression of an endogenous opioid system(s), regulating feeding rats, is not complete prior to this age. The present study was undertaken to examine the functional ontogeny of opioid receptors mediating opiate-induced feeding in rats. Rat pups, satiated with milk, were given intraperitoneal injections of the opiate receptor agonist, morphine, and were allowed free access to milk. Morphine stimulated the intake of milk at 3, 5, 7, 14 and 21 days of age, within 2 hr of injection. A time-course analysis in 7-day-old pups showed greater enhancement of intake between hours 2 and 4, than between hours 0 and 2, for large doses of morphine (0.3 and 1.0 mg/kg) suggesting that morphine-induced behavioral depression, which was observed early in the test session, confounded intake at earlier hours. Administration of the opiate receptor antagonist, naltrexone, produced no effect on intake of its own, but blocked the stimulation of intake by morphine in 5-day-old pups confirming that the effect of morphine on the intake of milk was mediated by opioid receptors. Thus, while a functional endogenous opioid system(s), regulating feeding in rats, is not fully mature until 14 days postpartum, the present results suggest that opioid receptors mediating feeding are functional very early in the postnatal development of the rat.

Aging↗
PubMed1990

Medial hypothalamic nuclei mediate serotonin's inhibitory effect on feeding behavior.

Previous studies have demonstrated that injection of serotonin (5-HT) into the paraventricular nucleus (PVN), specifically at the onset of the active feeding cycle, causes a strong and selective suppression of carbohydrate intake, while producing no change in fat intake and, in some cases, enhancing protein consumption. The purpose of the present investigation was to determine whether this selective inhibitory effect of 5-HT on macronutrient ingestion is localized to a specific brain region, perhaps the PVN, or whether it can also occur in other sites throughout the hypothalamus or in regions outside this structure. A total of 7 hypothalamic and 5 extrahypothalamic areas were examined in brain-cannulated, freely feeding rats maintained on pure macronutrient diets of protein, carbohydrate and fat. The effect of 5-HT, a selective suppression (-55%) of carbohydrate feeding, was replicated in the PVN with a relatively low dose of 2.5 nmoles. Tests in 11 other brain sites demonstrated that this action of 5-HT is not unique to the PVN but is anatomically localized to the medial nuclei of the hypothalamus. Sites outside the hypothalamus, namely, the amygdala, nucleus accumbens, septum, diagonal band of Broca and nucleus reuniens dorsal to the PVN, failed to exhibit any response to 5-HT injection. Within the hypothalamus, the ventromedial (VMN) and suprachiasmatic (SCN) nuclei each responded to 5-HT in a manner similar to the PVN, producing a suppression of carbohydrate intake (-50% to -70%) with little or no change in either protein, fat or total kcal intake. The dorsomedial nucleus showed a somewhat smaller response relative to these other medial hypothalamic areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Diurnal variations in the feeding responses to norepinephrine, neuropeptide Y and galanin in the PVN.

The feeding responses elicited by injection of norepinephrine (NE), neuropeptide Y (NPY) and galanin (GAL) into the paraventricular nucleus (PVN) were studied at two different times of the dark (active) cycle in male Sprague-Dawley rats maintained ad lib on pure nutrient diets. The feeding response elicited by NE in the PVN, characterized by a potent and selective stimulatory effect on ingestion of the carbohydrate diet, was significantly stronger during the early dark period (+11.7 kcal over vehicle baseline) relative to the late dark period (+7.6 kcal). A similar pattern of effects was observed with NPY in the PVN, which also selectively potentiated carbohydrate ingestion. The effects of GAL were different from those observed with NE and NPY. Whereas the total amount of food consumed after PVN GAL injection was similar in the early and late dark periods, the macronutrient selection patterns exhibited at these two times were different. During the early dark period, PVN GAL had a small stimulatory effect on carbohydrate, in addition to a strong enhancement of fat intake; in the late dark period, in contrast, GAL stimulated intake only of the fat diet. These findings may reflect differential functions of these hypothalamic neurotransmitters in controlling nutrient ingestion at different periods of the circadian cycle.

Animals↗
PubMed1990

Impact of hypothalamic d-norfenfluramine and peripheral d-fenfluramine injection on macronutrient intake in the rat.

Previous research with hypothalamic injection of serotonin (5-HT) has suggested that this monoamine may act within the medial hypothalamus to suppress carbohydrate intake in a selective, phasic and circadian-related fashion. To explore further the action of 5-HT in the brain, the present studies tested the serotonergic stimulants, d-norfenfluramine (DNF) and d-fenfluramine (DF), in freely feeding, brain-cannulated animals maintained on pure macronutrient diets (protein, carbohydrate and fat) and tested at different times of the diurnal cycle. The results show that administration of DNF into the paraventricular nucleus (PVN) potently influences appetite for a specific nutrient at a particular time of the light-dark cycle. Specifically, DNF injection at the onset of the nocturnal (active) period selectively and dose-dependently suppresses carbohydrate consumption, while leaving protein and fat intake unchanged. This drug, however, has no effect, even at high doses, on macronutrient intake in the middle and late h of the dark phase, strongly implicating a function for hypothalamic 5-HT in the control of carbohydrate ingestion at the beginning of the nocturnal cycle. The possibility that peripherally injected DF may act, in part, through this endogenous serotonergic system is supported by the additional finding that, at low doses of 0.06-0.5 mg/kg, DF preferentially modulates carbohydrate ingestion exclusively at the onset of the nocturnal period. However, at doses above 0.5 mg/kg, this compound produces a potent and general suppression of feeding of all macronutrients. In animals with brain cannulas aimed at different hypothalamic nuclei, the feeding-suppressive effect of DNF is found to be site specific; it is localized to the medial hypothalamic nuclei, including the ventromedial, suprachiasmatic and dorsomedial nuclei as well as the PVN. Serotonin in these nuclei may function to produce satiety specific for carbohydrate and, through the suprachiasmatic nucleus, control energy intake in a circadian-related manner.

Animals↗
PubMed1990

The role of serotonin in eating disorders.

Recent pharmacological studies have more precisely characterised the nature of the inhibitory effect of brain serotonin (5-hydroxytryptamine) on feeding behaviour. Thus, the brain sites and receptors involved have been identified, and a possible physiological role of endogenous serotonin in controlling natural patterns of eating and nutrient selection has been defined. The medial hypothalamus is believed to be a critical location in the mediation of serotonin's action. Specifically, the paraventricular and ventromedial nuclei are known to be involved in controlling energy balance, while the suprachiasmatic nucleus determines circadian patterns of eating. Serotonergic stimulation of these 3 nuclei with exogenous serotonin or drugs that release endogenous serotonin, preferentially reduces carbohydrate intake in naturally feeding animals through satiety mechanisms involved in the termination of feeding. This phenomenon is mediated by serotonin and possibly serotonin receptors, in contrast to serotonin autoreceptors which potentiate feeding possibly by inhibiting serotonin release. The activity of serotonergic function in the medial hypothalamus exhibits a circadian rhythm which is characterised by a peak at the beginning of the active cycle when the motivation to eat is strongest and is triggered by deficits in energy stores. At this time, carbohydrate is found to be the naturally preferred macronutrient, and it appears that serotonin becomes most activated under these conditions to terminate the carbohydrate-rich meal, possibly by activating satiety neurons localised in the medial hypothalamus. In this process, serotonin may interact antagonistically with noradrenaline (norepinephrine) and its alpha 2-noradrenergic receptors that normally function to enhance carbohydrate intake at the onset of the natural feeding cycle. Moreover, while inducing satiety for carbohydrate, serotonin may also play a role in switching the animal's preference towards protein. The regulation of this macronutrient is closely linked to that of carbohydrate, and it is normally preferred in the second meal of the natural feeding cycle. Most of the pharmacological evidence to date generally supports the hypothesis that disturbances in serotonin function occur in eating disorders. Decreases in plasma tryptophan, urinary 5-hydroxyindoleacetic acid (5-HIAA), platelet serotonin binding and basal cerebrospinal fluid 5-HIAA in anorexia nervosa normalise upon weight restoration and appear to be starvation effects. These alterations in serotonergic function may however perpetuate the symptomatology of anorexia nervosa once the illness is set in motion. Some drugs which in part affect serotonergic function facilitate weight gain in conjunction with an integrated psychotherapeutic and behavioural programme. Patients with bulimia nervosa, regardless of the presence of anorexia nervosa or major depression, who have been relatively weight stable and free of binge/vomit episodes for at least 3 weeks, have significantly blunted prolactin responses to the serotonin agonists. These findings indicate that post-synaptic responsiveness in hypothalamic-pituitary serotonergic pathways is reduced in bulimia. Similar alterations in other serotonin pathways at or above the level of the hypothalamus may contribute to binge eating and other behavioural symptoms in bulimic patients. The clinical response to several psychotropic agents known to potentiate serotonergic transmission further substantiates a serotonin dysregulation hypothesis of bulimia nervosa.(ABSTRACT TRUNCATED AT 400 WORDS)

Feeding and Eating Disorders↗
PubMed1989

Medial hypothalamic serotonin: role in circadian patterns of feeding and macronutrient selection.

Hypothalamic serotonin (5-HT) is believed to have an inhibitory effect on food intake in a variety of species. To define more precisely the nature of this effect, this study investigated the effects of medial hypothalamic 5-HT injection on natural patterns of macronutrient intake in freely feeding rats. Serotonin (5-20 nmol) was injected directly into the paraventricular nucleus (PVN) of brain-cannulated rats maintained ad libitum on pure macronutrient diets, protein, carbohydrate and fat, and measurements of nutrient intake were taken one hour later. To assess whether the action of 5-HT on macronutrient intake varies across the light-dark cycle, these tests were conducted at 3 different times in the nocturnal feeding period, during hours 1, 6 and 11 after lights out. The results demonstrate that the suppressive effect of PVN 5-HT on food intake is dose dependent, nutrient selective, as well as time dependent. Specifically, PVN injection of 5-HT, at all doses tested, was effective at only one time of the nocturnal cycle, namely, at the onset of the active, dark period. While no behavioral effect of 5-HT was detected in the middle and late phases of the dark, a strong, dose-dependent reduction of nutrient intake was revealed immediately after lights out. This suppressive effect was characterized by a highly selective decrease in carbohydrate intake, along with a significant enhancement in preference for protein, as well as for fat, and little change in total caloric intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Suppression of neuropeptide Y-elicited eating by adrenalectomy or hypophysectomy: reversal with corticosterone.

Neuropeptide Y (NPY) injected into the paraventricular hypothalamus (PVN) stimulates a robust eating response in the satiated rat. To examine whether the NPY-feeding system interacts with the pituitary-adrenal axis, the eating response to PVN injections of NPY (78 pmol) was tested in adult male rats before and after sham surgery, adrenalectomy (ADX), hypophysectomy (HYPX), and/or corticosterone (CORT) replacement therapy. In unoperated or sham groups, NPY elicited 5.7-8.8 g of food intake in 1 h as compared to 0.4-1.1 g for vehicle-injected animals. In ADX groups, the NPY-elicited response was reduced by 60-71%, to between 2.4 and 2.8 g. Likewise, the average response of the HYPX group was reduced by 69%, to 1.7 g. Corticosterone replacement, via subcutaneous implant of a 100 mg CORT pellet, normalized the NPY-induced feeding response in both the ADX and HYPX groups. These findings suggest that the hypothalamic NPY-feeding system is largely dependent upon circulating CORT and that no other adrenal or pituitary hormone is essential.

Animals↗
PubMed1989

Corticosterone-dependent alterations in utilization of catecholamines in discrete areas of rat brain.

This study investigated the impact of chronic adrenalectomy (ADX), and subsequent corticosterone (CORT) replacement to ADX rats, on brain levels of norepinephrine (NE) and dopamine (DA) and their extent of depletion after alpha-methyl-p-tyrosine (alpha-MpT) administration. Seven discrete hypothalamic areas, namely, the paraventricular nucleus (PVN), medial preoptic nucleus (POM), dorsomedial nucleus (DMN), ventromedial hypothalamus (VMH), perifornical lateral hypothalamus (PLH), supraoptic nucleus (SON), and arcuate nucleus/median eminence (ARC-ME), were examined. The steady-state content of NE and DA in all areas remained essentially unaltered 7 days after ablation of the adrenal glands, as well as after subsequent CORT replacement therapy in ADX rats. However, ADX, which reduced circulating CORT levels to 0.3 microgram % as compared to greater than 3.0 micrograms % in sham rats, caused a significant increase in the depletion of NE following alpha-MpT treatment, in 4 out of the 7 brain sites examined (PVN, PLH, DMN and ARC-ME). In these brain sites, the NE turnover rate (K, pg/microgram protein/h) and rate constant (K, h-1) increased following ADX. The chronic subcutaneous CORT implant (200 mg), which raised circulating CORT levels of ADX rats to 11 micrograms %, prevented this enhancement of NE turnover in the PVN, PLH and ARC-ME, but not the DMN. Unlike NE, DA utilization in the 7 discrete hypothalamic areas of alpha-MpT-treated rats remained unaltered after ablation of the adrenal glands, as well as after the CORT replacement therapy in ADX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1989

Norepinephrine in the paraventricular nucleus stimulates corticosterone release.

Hypothalamic cells containing corticotropin-releasing factor are believed to be densely innervated by noradrenergic terminals. However, the role of norepinephrine (NE) in the control of the hypothalamo-pituitary-adrenal axis has remained undefined, with both excitatory and inhibitory effects suggested by the literature. The present experiments tested the effects of direct hypothalamic infusion of NE on the release of corticosterone (CORT) in awake and freely moving rats. Norepinephrine infusion into the paraventricular nucleus (PVN) produced a dose-dependent increase in circulating levels of CORT. In a mapping study, this stimulatory effect of NE was found to be anatomically localized. The strongest rise in CORT levels (up to 12 micrograms%) was observed after injection into the PVN, where NE acted in a dose-dependent fashion. A somewhat smaller effect was also detected with NE in the dorsomedial nucleus, while no response occurred after injection just dorsal to the PVN, into the ventromedial or supraoptic nuclei, or into the lateral or posterior hypothalamus. Serotonin infusion into the PVN produced a small but statistically reliable increase in circulating CORT levels. However, dopamine injection into this nucleus had no observable effect. These results agree with recent studies suggesting an excitatory function of PVN NE in the pituitary-adrenal axis.

Animals↗
PubMed1989

Patterns of extracellular norepinephrine in the paraventricular hypothalamus: relationship to circadian rhythm and deprivation-induced eating behavior.

In order to clarify the physiological role of norepinephrine (NE) in the hypothalamic paraventricular nucleus (PVN), changes in extracellular levels of endogenous NE were measured in 11 freely-moving rats using microdialysis and high pressure liquid chromatography with electrochemical detection. To determine whether there was a circadian pattern of extracellular NE in freely-eating subjects, samples of dialysate from the vicinity of the PVN were collected and assayed for NE every 2 hrs for 48 hrs. The pattern of NE averaged across subjects was similar during both 24-hr periods, with a reliable peak at the beginning of the dark cycle and relatively stable levels at all other times. When these animals were subsequently deprived of food for 24 hrs, a gradual rise in extracellular NE was observed, ultimately increasing to 215% of the predeprivation level. When the animals were refed and NE measurements were continued at more frequent intervals, extracellular levels were found to decline during the first 20 min of eating, as well as over the next 3 hrs as food intake diminished. These patterns of extracellular NE, together with previous evidence, suggest that endogenous NE in the PVN plays a role in the initiation and/or maintenance of normal eating behavior at the beginning of the nocturnal feeding period, as well as after food deprivation.

Animals↗