Search PubMed⌕ Search

Biomedical subjects

S F Leibowitz

Publications and source records attributed to S F Leibowitz.

At least 109 records · Page 6Linked to original sources
PubMed1987

Hypothalamic neurotransmitters in relation to normal and disturbed eating patterns.

An integrated hypothesis for explaining eating behavior must consider the organism as a whole, the multiple brain neurotransmitters and structures involved, and the diverse variables that have impact on the expression of the behavior. In this review, we will examine a variety of brain monoamines and neuropeptides, in terms of their impact on eating, and also relate these neurochemical systems to peripheral autonomic and endocrine functions. We will propose how these central and peripheral systems may interact under normal and generally stable conditions, as well as how they may help to maintain energy or nutritional homeostasis under stressful conditions, in particular, food deprivation.

Brain↗
PubMed1986

Relationships between medial hypothalamic alpha 2-receptor binding, norepinephrine, and circulating glucose.

These experiments examine the dependence of medial hypothalamic alpha 2-receptor binding on the availability of circulating glucose. Food deprivation and tolbutamide-induced hypoglycemia both diminished alpha 2-binding. These binding results were highly correlated with serum glucose levels. Prevention of tolbutamide hypoglycemia by concomitant injections of dextrose blocked the effects on alpha 2-binding. Injection of norepinephrine into the medial hypothalamic sites that normally elicit feeding behavior elevated serum glucose. These results suggest a homeostasis for control of glucose in a hypothalamic feeding system.

Animals↗
PubMed1986

Impact of circulating corticosterone on alpha 1- and alpha 2-noradrenergic receptors in discrete brain areas.

The impact of adrenalectomy (ADX) and subsequent corticosterone(CORT) replacement, on the binding of [3H]p-aminoclonidine to alpha 2-noradrenergic receptors and [3H]prazosin to alpha 1-noradrenergic receptors, was studied in 8 discrete hypothalamic and 5 extra-hypothalamic areas of rats. With little change in extra-hypothalamic receptors, ADX produced a large CORT-reversible decrease in alpha 2-receptor binding specifically within the hypothalamic paraventricular nucleus (PVN) and a CORT-reversible increase within the supraoptic nucleus. alpha 1-Noradrenergic receptors, in contrast, were generally unaffected by ADX. This and other evidence leads us to propose a potential modulatory influence of circulating CORT on hypothalamic alpha 2 receptors and a specific function for this CORT-alpha 2 receptor interaction specifically within the PVN, in the control of eating behavior.

Adrenalectomy↗
PubMed1986

Diurnal rhythm of alpha 2-noradrenergic receptors in the paraventricular nucleus and other brain areas: relation to circulating corticosterone and feeding behavior.

The paraventricular nucleus alpha 2-noradrenergic system and the glucocorticoid hormone, corticosterone, are known to modulate feeding behavior and exhibit a circadian pattern which may be related to the natural periodicity of feeding in the rat. The results of the present study indicate that the binding of [3H]p-aminoclonidine to alpha 2-noradrenergic receptors specifically in the paraventricular nucleus varies concomitantly with plasma corticosterone levels, as well as spontaneous feeding. A monophasic peak of paraventricular noradrenergic receptor binding is detected at the onset of the dark period, when corticosterone levels are highest and feeding is initiated. On the other hand, the supraoptic nucleus exhibits the reverse diurnal pattern, i.e., a significant decline of [3H]p-aminoclonidine binding at the onset of the dark period. Other hypothalamic and extra-hypothalamic areas fail to show significant changes in alpha 2-noradrenergic receptors as a function of the diurnal cycle. This study supports other evidence indicating a close interaction between circulating corticosterone and alpha 2-noradrenergic receptors in specific hypothalamic areas. It also reveals a potential importance for this interaction in control of the natural feeding rhythm.

Animals↗
PubMed1986

Destruction of noradrenergic innervation to the paraventricular nucleus: deficits in food intake, macronutrient selection, and compensatory eating after food deprivation.

Norepinephrine (NE) injected into the paraventricular nucleus (PVN) has a stimulatory effect on feeding behavior and is found to selectively enhance preference for carbohydrate in the rat. The present experiments were conducted to assess the impact of chronic depletion of NE within the PVN on food intake and appetite regulation. The catecholamine (CA) neurotoxin, 6-hydroxydopamine (6-OHDA), when administered into the PVN, produced a significant depletion of PVN NE in association with a variety of behavioral changes. The immediate consequence of the neurotoxin lesion was a dramatic increase in 24-hr food intake, attributed predominantly to a preferential increase in carbohydrate and fat consumption. The long-term effects related to CA depletion were a deficit in daily food consumption, particularly of carbohydrate (-42%). Although animals with diminished PVN NE maintained a normal diurnal feeding pattern, they failed to exhibit the increased ingestion of an energy-rich carbohydrate diet which rats normally show during the dark period of the diurnal cycle. Rats injected with 6-OHDA directly into the PVN exhibited a normal response to glucoprivic challenge, but demonstrated a deficit in their ability to produce compensatory feeding, particularly of carbohydrate and fat, in response to food deprivation. These findings suggest a specific function for PVN noradrenergic mechanisms in normal energy repletion when body energy stores are reduced.

Adaptation, Physiological↗
PubMed1986

Medial hypothalamic serotonin: effects on deprivation and norepinephrine-induced eating.

Evidence to date suggests an inhibitory role for serotonin (5-HT) in the regulation of feeding behavior. In the present study, hypothalamic 5-HT was investigated for its anorexic potency under different feeding conditions. In fasted rats, 5-HT (1.1-4.4 micrograms) injected into the hypothalamic paraventricular nucleus (PVN), produced a reliable dose-dependent reduction in food consumption. Under satiated conditions, this inhibitory effect was significantly larger and apparent at lower doses (down to 0.1 micrograms), in animals induced to eat by PVN injection of norepinephrine (NE). Tests with receptor antagonists, injected into the PVN immediately prior to 5-HT, revealed a dose-dependent blockade of 5-HT's action by the serotonergic blockers, metergoline, methysergide and cinanserin. While the effect of 5-HT was somewhat attenuated by administration of certain beta-adrenergic and phenothiazine-type dopamine receptor antagonists, 5-HT was totally resistant to the actions of more selective dopamine blockers and of the cholinergic and histaminergic antagonists, atropine and dexbrompheniramine. PVN injection of various serotonergic compounds, known to inhibit feeding when peripherally administered, also suppressed NE-induced feeding in a dose-related manner (fluoxetine = dl-norfenfluramine greater than quipazine greater than chlorimipramine greater than dl-fenfluramine). Further tests with PVN administration of the dextro isomer and metabolite of fenfluramine showed a considerably stronger inhibitory effect with d-norfenfluramine as compared to dexfenfluramine, and a particular effectiveness of peripherally injected dexfenfluramine in NE-injected rats, at doses at least 10-fold higher than centrally effective doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Morphine-elicited feeding: diurnal rhythm, circulating corticosterone and macronutrient selection.

The present study examined the feeding response elicited by morphine, injected either intraperitoneally (IP), or into the paraventricular nucleus (PVN), as a function of diurnal cycle and also in adrenalectomized rats with or without peripheral corticosterone replacement. In animals maintained on a single diet of chow, milk and sugar, a diurnal rhythm in both the peripheral and central morphine-induced feeding responses was observed, with a stronger eating effect occurring in the early dark hours compared with the responses obtained in the early light period. Adrenalectomy significantly reduced the feeding induced by morphine injected IP or into the PVN, and acute corticosterone replacement restored the response. Rats maintained on a self-selection feeding paradigm, with carbohydrate, protein and fat simultaneously available, exhibited a significant increase in total caloric intake after morphine injected IP, along with a preferential increase in the consumption of protein and fat. Adrenalectomy nearly abolished this stimulatory effect of morphine on total intake and altered the diet preference pattern. These findings underscore the importance of corticosterone in the feeding response of morphine injected peripherally or specifically into the PVN. The present findings suggest that corticosterone plays an important role in determining the diurnal rhythm of opiate-induced feeding and the function of endogenous opioids in the regulation of energy balance.

Adrenalectomy↗
PubMed1986

Morphine-stimulated feeding: analysis of macronutrient selection and paraventricular nucleus lesions.

The hypothalamic paraventricular nucleus (PVN) has been found to be sensitive to the feeding stimulatory effects of opiates. The present experiments investigated the effect of systemic morphine (2 mg/kg) on macronutrient selection in freely-feeding and food-restricted rats and assessed the impact of PVN electrolytic and 6-hydroxydopamine lesions on the rats' ability to respond to peripheral morphine injection. In satiated rats, maintained ad lib on pure macronutrient diets, morphine increased food intake. This effect was associated with a preferential increase in protein ingestion; carbohydrate consumption, compared with fat and protein intake, was least affected. In food-restricted rats, permitted to eat for 6 hr, morphine instead produced a particular preference for fat, with no significant enhancement of total calorie intake. While PVN 6-hydroxydopamine lesions, which depleted PVN catecholamine levels by 70%, failed to alter morphine-stimulated feeding, electrolytic lesions of the PVN significantly attenuated this response, particularly protein and fat ingestion. This suggests that opiate-induced feeding may, in part, be mediated through the PVN, which is known to have an important function in the control of food ingestion.

Animals↗
PubMed1986

Amphetamine-induced anorexia: analysis with hypothalamic lesions and knife cuts.

The present study examined the hypotheses that the midlateral perifornical region of the hypothalamus (PFH), at the level of the ventromedial nucleus, plays a crucial role in amphetamine (AMPH)-induced anorexia and that mediating fibers ascending to this brain region follow a midlateral course through the caudal hypothalamus. Electrolytic lesions that destroyed the PFH region attenuated the feeding suppression induced by intraperitoneal administration of AMPH. Lesions placed anterior, dorsal, or medial to this region, in contrast, did not decrease AMPH's effect. The medially-placed paraventricular nucleus lesion, in fact, enhanced drug response. Midlateral coronal wire-knife cuts in the caudal hypothalamus also attenuated AMPH anorexia. The crucial midlateral caudal hypothalamic cut also disrupted anorexia induced by direct injection of AMPH into the PFH area. The results obtained from the lesion data support the hypothesis that the PFH region is essential to AMPH's suppressive effect upon feeding, and the KC data suggest that crucial catecholamine fibers mediating this drug response ascend specifically through the midlateral portion of the hypothalamus.

Adrenergic Fibers↗
PubMed1986

Impact of food deprivation on alpha 1- and alpha 2-noradrenergic receptors in the paraventricular nucleus and other hypothalamic areas.

Hypothalamic norepinephrine may modulate normal eating behavior through activation of alpha 2-noradrenergic receptors, localized in the paraventricular nucleus (PVN). We investigated whether these receptors, which stimulate food ingestion, may in turn be altered by the nutritional state of the organism. Thus the impact of food deprivation, on the specific binding of [3H]-p-aminoclonidine ([3H]PAC) to alpha 2-noradrenergic receptors in discrete hypothalamic areas, was examined in rats. The results of our first experiment revealed that 48 hr food deprivation reduced (by 50%) the maximum number of binding sites (Bmax) of the high affinity component of [3H]PAC binding to alpha 2 receptors. This effect occurred exclusively in the medial hypothalamus (which includes the PVN), without any change in the affinity (Kd) of these receptors. A smaller decline was seen in the low affinity binding sites of the medial hypothalamus, whereas no changes were observed in the density or affinity of the high and low affinity alpha 2 receptor sites in the lateral hypothalamus or frontal cortex. The alpha 1-noradrenergic receptor sites, as defined by [3H]prazosin and [3H]WB-4101 binding, were also unaffected in the different brain areas by 48 hr food deprivation. An additional analysis of alpha 2 receptors in discrete hypothalamic nuclei demonstrated that the deprivation-induced decline in alpha 2-receptor binding: occurred specifically in the PVN; was apparent after as little as 3 hr food deprivation; and occurred only when this brief deprivation fell at the onset of the dark cycle, as opposed to at the end of the dark cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Hypothalamic serotonin in the control of meal patterns and macronutrient selection.

Serotonin (5-HT) is believed to have an inhibitory influence over feeding behavior. The present experiments were designed to investigate the effects of hypothalamic 5-HT on spontaneously motivated feeding and appetite regulation. Freely-feeding rats were injected with 5-HT or norfenfluramine (NORFENF) directly into the paraventricular hypothalamus (PVN), and precise changes in feeding behavior were monitored by a computer. Following PVN 5-HT or NORFENF injection, animals exhibited a marked suppression in food intake, associated with a decrease in meal size, duration and eating rate, and no change in the frequency of meals consumed. This suggests that brain 5-HT may influence primarily the induction of satiety rather than the suppression of hunger. The effect of drugs presumed to affect brain 5-HT transmission on diet selection was also investigated in groups of rats injected centrally with 5-HT or NORFENF or peripherally with either fenfluramine, quipazine or cyproheptadine. In a series of 2-diet tests, rats centrally injected with 5-HT or NORFENF exhibited a selective suppression of the carbohydrate-rich diets. In animals provided with three pure macronutrient diets, protein, carbohydrate, and fat, systemic administration of serotonergic agents had its greatest impact on fat and carbohydrate ingestion, as compared to protein consumption. These findings support a role for hypothalamic 5-HT in modulating meal patterns and appetite for particular macronutrients.

Animals↗
PubMed1986

Amphetamine: effects on meal patterns and macronutrient selection.

Catecholaminergic systems, specifically in the region of the lateral perifornical hypothalamus (PFH), have been linked to the inhibition of feeding behavior. The present studies examined the effects of d-amphetamine (AMPH), which is believed to act through the release of endogenous catecholamines (CAs), on spontaneous feeding and appetite regulation in rats. Injection of AMPH directly into the PFH caused a marked suppression of food intake; changes in computer-monitored meal patterns were characterized by an increase in the latency to meal onset and a consequent reduction in meal size and duration. This suggests that hypothalamic AMPH administration may influence primarily the initiation, rather than the termination, of feeding. In other experiments, chronic infusion of AMPH directly into the PFH was shown to suppress 24 hr food intake and body weight gain, indicating the effectiveness of lateral hypothalamic CA stimulation in overriding normal long-term patterns of feeding. The effect of hypothalamic CA stimulation on macronutrient selection was also investigated in groups of rats injected either centrally or peripherally with AMPH, or centrally with the CA agonists, dopamine and epinephrine. Each of these manipulations caused a strong inhibition of protein intake with no effect on carbohydrate, and only a mild suppression of fat ingestion after peripheral AMPH. These selective effects of AMPH on feeding patterns and diet choice, provide support for a role of CA innervation to the lateral hypothalamus in the modulation of natural feeding behavior and macronutrient selection.

Animals↗
PubMed1986

Brain serotonin and eating behavior.

Studies indicate that hypothalamic monoamine systems involved in the control of food intake have specific effects on temporal feeding patterns and on appetite for specific macronutrients. Based on the evidence obtained in rats, it is proposed that serotonin acts, in part, through a satiety mechanism of the medial hypothalamus, to reduce ingestion of carbohydrate while sparing protein intake. In controlling the ratio of carbohydrate to protein intake, this serotonergic system, which is responsive to the anorectic agent fenfluramine, is believed to function in direct opposition to the alpha 2-noradrenergic system of the paraventricular nucleus, which inhibits satiety for carbohydrate and thereby potentiates the size of carbohydrate meals. This serotonergic system may also indirectly oppose the catecholaminergic systems of the lateral hypothalamus, which mediate amphetamine anorexia and which inhibit a hunger-stimulating system for protein intake, thereby delaying the initiation of protein meals. Examination of the rats' normal eating patterns, in conjunction with particular biochemical analyses, has indicated specific points in the circadian eating cycle where these hypothalamic monoamine systems, in association with changes in circulating hormones and nutrients, may be physiologically activated.

Amphetamine↗
PubMed1986

Alpha 2-noradrenergic feeding rhythm in paraventricular nucleus: relation to corticosterone.

The feeding response induced by the paraventricular nucleus (PVN) injection of norepinephrine (NE) in rats has been shown to correlate positively in magnitude with the level of circulating corticosterone. The present study examined the feeding responses induced by NE and clonidine (CLON) injected into the PVN and CLON injected intraperitoneally, as a function of diurnal cycle and also in adrenalectomized animals with and without peripheral corticosterone replacement. A periodicity in the effectiveness of PVN-injected NE and CLON, as well as intraperitoneal CLON, was observed, with a significantly stronger eating response occurring near the onset of dark period compared with the response produced in the early light period. Adrenalectomy abolished the feeding induced by each of these alpha-noradrenergic agonists, and acute corticosterone replacement restored the response. The feeding induced by intraperitoneally injected 2-deoxy-D-glucose was unaffected. These findings indicate the importance of corticosterone to the action of peripherally and centrally administered alpha-noradrenergic agonists and also suggest that the diurnal rhythm of corticosterone plays an important role in determining the rhythm for the feeding response induced by PVN alpha 2-noradrenergic activation.

Adrenalectomy↗
PubMed1986

Interaction between corticosterone and alpha-2-noradrenergic system of the paraventricular nucleus in relation to feeding behavior.

Food consumption elicited by injection of norepinephrine (NE) into the paraventricular nucleus (PVN) of satiated rats has been shown to be dependent on the glucocorticoid corticosterone. To determine the specific nature of this dependence of NE-induced feeding on corticosterone, the efficacy of PVN-injected NE and its interaction with peripherally administered corticosterone was examined in adrenalectomized rats. NE, at doses ranging from 10 to 160 nmol, failed to elicit a reliable feeding response in these adrenalectomized animals. This loss of noradrenergic responsiveness developed at least as early as 4 h after adrenalectomy and continued until the end of the test sequence 6-8 weeks post-surgery. Single subcutaneous injections of corticosterone, administered to adrenalectomized rats, significantly restored the NE feeding response when injected 15-120 min prior to NE PVN injection, but not when administered 5 min before. Corticosterone was effective at doses of 0.5-4.0 mg/kg. Tests with other steroid hormones, namely, the synthetic glucocorticoid dexamethasone, the mineralocorticoid deoxycorticosterone, and the gonadal hormones testosterone and progesterone, were generally ineffective in restoring the sensitivity of the PVN to noradrenergic stimulation. Radioimmunoassay of circulating corticosterone in adrenalectomized rats, as a function of dose and time after injection of corticosterone, indicated that physiological levels of the hormone, at least 3 micrograms%, are required for a patent behavioral effect. These findings demonstrate a specific, sensitive, and rapid dependence of the PVN alpha 2-noradrenergic eating response on circulating corticosterone.

Adrenalectomy↗
PubMed1986

Brain monoamines and peptides: role in the control of eating behavior.

Studies of brain monoamines and neuropeptides have provided extensive evidence in support of their role in the control of normal eating behavior. In this process, the medial and lateral portions of the hypothalamus, working in conjunction with forebrain and hindbrain sites and with peripheral autonomic-endocrine systems, have a critical responsibility in balancing signals for hunger and satiety. Via its rich and biologically active neurotransmitter substances, the hypothalamus monitors and integrates the complex sensory and metabolic input concerning the nutritional status of the organism and transduces this information into appropriate quantitative and qualitative adjustments in food intake. The specific neurotransmitters for which there is the most extensive evidence for a physiological function include the eating-stimulatory substances norepinephrine (alpha 2), opioid peptides, pancreatic polypeptides, growth hormone-releasing factor, and gamma-aminobutyric acid; the eating-inhibitory substances dopamine, epinephrine, serotonin, cholecystokinin, neurotensin, calcitonin, glucagon, and corticotropin-releasing factor; and possibly other gut-brain peptides. From biochemical, pharmacological, and anatomical studies, hypotheses have been generated to explain the role of these various monoamines and neuropeptides in controlling total energy intake, in determining the amount and pattern of macronutrient selection, and in maintaining normal energy and nutrient stores under fluctuating conditions within the external environment.

Animals↗