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Biomedical subjects

S F Leibowitz

Publications and source records attributed to S F Leibowitz.

At least 127 records · Page 7Linked to original sources
PubMed1985

Efferent projections from the paraventricular nucleus mediating alpha 2-noradrenergic feeding.

Feeding behavior elicited by central injection of the alpha-noradrenergic agonists, norepinephrine (NE) and clonidine (CLON), are believed to be mediated via postsynaptic alpha 2-type receptors located in the paraventricular nucleus (PVN). To map the course taken by essential efferent (descending) fibers of this PVN system for noradrenergically-stimulated feeding, the impact of diencephalic and lower brainstem coronal knife cuts, on the responses elicited by PVN-injected NE and CLON, was assessed. Rats that sustained damage in the periventricular gray area of the caudal thalamus and midbrain exhibited significant losses in feeding elicited by PVN injections of these drugs. In the case of animals with midbrain periventricular gray knife cuts, a significant increase in daily food intake was also observed, and this increase was positively correlated in magnitude with the attenuation of NE-induced feeding. This decrease in sensitivity to alpha 2-noradrenergic stimulation occurred with discrete periventricular knife cuts extending only 0.5 mm lateral to midline. In contrast, large ventral or lateral coronal knife cuts throughout the dorsal and ventral midbrain tegmentum left intact NE- and CLON-induced feeding. These findings provide evidence for localization of anatomical substrates which underlie PVN alpha 2-noradrenergic feeding. The efferent fibers of this system appear to exit from the PVN in a dorsomedial direction and course through the thalamic periventricular area. As this projection descends into the midbrain, it remains quite medial, maintaining this position throughout the midbrain central gray substance. At the level of the pons, just rostral to the locus coeruleus, this fiber projection appears to course ventrolaterally into the dorsolateral pontine tegmentum and possibly continue towards the dorsal vagal complex of the dorsomedial medulla.

Animals↗
PubMed1985

Suppression of norepinephrine-elicited feeding by neurotensin: evidence for behavioral, anatomical and pharmacological specificity.

Neurotensin (NT) injected into the paraventricular hypothalamic nucleus (PVN) has been shown to suppress feeding behavior. To investigate whether this suppression generalizes to feeding elicited by norepinephrine injection, rats with bilateral PVN cannulas were injected with NT (3.0 nmol/cannula) or vehicle followed by norepinephrine (20.0 nmol/cannula). Pretreatment with NT caused a 48% reduction in feeding elicited by norepinephrine. To determine whether NT's effect resulted from non-specific behavioral effects or leakage into the periphery, NT (0.25, 1.25 or 6.0 nmol) was injected ipsilateral or contralateral to a unilateral norepinephrine (40.0 nmol) injection. Ipsilateral NT produced a dose-dependent suppression of norepinephrine-elicited feeding which was significantly greater than the effect of contralateral NT, suggesting that NT's effect was at least partially behaviorally and anatomically specific. To investigate the pharmacological specificity of the suppression, rats that ate in response to PVN norepinephrine (40.0 nmol) were given prior injections of NT or one of six NT fragments at 0.25, 1.25, 6.0 or 30.0 nmol. NT and the C-terminal fragments 3-13 and 6-13 caused a dose-dependent suppression of feeding. In contrast, none of the N-terminal fragments (i.e. 1-8, 1-11 or 1-12) were effective. This specificity rules out non-specific changes in parameters such as pH or osmotic pressure and suggests that the anorectic effect may have been mediated by NT receptors.

Animals↗
PubMed1985

Postsynaptic alpha 2-noradrenergic receptors mediate feeding induced by paraventricular nucleus injection of norepinephrine and clonidine.

This study examines the feeding response induced by hypothalamic noradrenergic stimulation, in terms of the type and synaptic position of its mediating receptor. Tests with norepinephrine or the alpha 2 receptor agonist clonidine, injected into the area of the paraventricular nucleus (PVN), revealed a potent feeding response in satiated animals. This response by either agonist was blocked, in a dose-dependent fashion, by local injection of the alpha 2-noradrenergic antagonists, rauwolscine and yohimbine. It was also blocked by the general antagonist, phentolamine. In contrast, it was unaffected by hypothalamic injection of the alpha 1-noradrenergic antagonists, prazosin and corynanthine. These results indicate that feeding elicited by noradrenergic stimulation in the region of the PVN is mediated through alpha 2-type receptors. These alpha 2 receptors appear to be located postsynaptically, since the effectiveness of clonidine in eliciting eating was undisturbed by prior injection of the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine.

Animals↗
PubMed1985

Clonidine effects on catecholamine levels and turnover in discrete hypothalamic and extra-hypothalamic areas.

In rats treated with alpha-methyl-p-tyrosine (alpha-MpT) or saline, the effects of clonidine on the levels and turnover of norepinephrine (NE), epinephrine (EPI) and dopamine (DA) were analyzed in microdissected regions of the hypothalamus and extra-hypothalamic structures. In 7 of the 9 brain sites examined (namely dorsomedial nucleus, ventromedial nucleus, medial preoptic area, midlateral perifornical hypothalamus, frontal cortex, dorsal hippocampus and cerebellum), clonidine (50 micrograms/kg) caused a significant decrease in NE turnover, with no change in steady-state levels. In the two remaining areas, namely the hypothalamic paraventricular nucleus and the locus coeruleus, clonidine produced different patterns of effects. In the paraventricular nucleus (PVN), clonidine significantly reduced NE content in saline-treated rats, and in rats injected with alpha-MpT + clonidine, no further change in NE concentration was observed. In the locus coeruleus, both NE levels and turnover were unaltered. Epinephrine and DA turnover, in contrast to NE turnover, was unaffected by clonidine in all brain areas, with the exception of the midlateral hypothalamus, where the alpha-MpT-induced depletion of EPI and DA was totally reversed by clonidine, and in the frontal cortex, where DA turnover was also significantly reduced. These data are discussed relative to the proposed physiological actions of clonidine in the hypothalamus.

Animals↗
PubMed1985

Deficits in the control of food intake after hypothalamic paraventricular nucleus lesions.

Noradrenergic mechanisms of the hypothalamic paraventricular nucleus (PVN) have been shown to play an important role in the stimulation of feeding To determine the influence of this nucleus in monitoring and controlling responses to physiological and pharmacological challenges, PVN electrolytic lesion rats were tested for their behavioral responsiveness to agents known to affect the alpha-2 noradrenergic system as well as release of corticosterone, and to short- and long-term periods of food deprivation. Discrete lesions of the PVN produced enhanced feeding, particularly of carbohydrate, in freely-feeding rats maintained on a macronutrient self-selection paradigm. Lesion rats demonstrated a behavioral deficit in food intake regulation (a decrease in carbohydrate ingestion) in response to 5-hr and 24-hr fasts, showed a disturbance in circadian feeding, and exhibited a dramatic decrease in circulating corticosterone. However, feeding in response to 2-deoxy-D-glucose and insulin remained intact, suggesting that noradrenergic receptors within the PVN are not involved in the mediation of glucoprivic-induced feeding.

Animals↗
PubMed1985

Role of hypothalamic norepinephrine in control of meal patterns.

Feeding behavior has been shown to be strongly affected by central administration of catecholamines. In this study, we examined in freely-feeding rats the effect of hypothalamic norepinephrine (NE) injections on the basic parameters of spontaneous ingestion. Precise changes in feeding behavior in rats maintained on ad lib food and water intake were monitored by a PDP 8 computer connected to an apparatus capable of measuring licks and bites of food. Injections of NE were administered into the hypothalamic paraventricular nucleus, the most sensitive brain area for the elicitation of feeding through direct alpha-noradrenergic stimulation. In tests conducted under both light and dark conditions, NE facilitated food intake, primarily by an increase in meal size rather than meal frequency. The first meal after injection was increased in size and duration; the rate of eating was also enhanced. Whereas the following intermeal interval was significantly larger, subsequent meals and intermeal intervals appeared generally unaffected. This evidence is consistent with the proposal of a role for hypothalamic NE in the maintenance, rather than initiation, of feeding behavior in freely-feeding rats.

Animals↗
PubMed1985

Hypothalamic sites sensitive to morphine and naloxone: effects on feeding behavior.

Three experiments investigated the feeding response of brain cannulated rats to hypothalamic injection of norepinephrine (NE), the opiate agonist morphine sulfate (MO) and the opiate antagonist naloxone (NAL). Morphine elicited feeding in a dose-dependent manner when injected into the paraventricular nucleus (PVN) of satiated rats, at doses of 0.78 to 100 nmoles, with a threshold dose of 1.56 nmoles. Naloxone, at doses of 3.13 to 200 nmoles, was injected into the PVN of food-deprived rats and was found to produce a dose-dependent suppression of feeding (threshold dose of 6.25 nmoles). Animals with brain cannulas aimed at the PVN, the perifornical hypothalamus (PFH), the dorsomedial (DMN) and ventromedial (VNM) nuclei were compared for their sensitivity to the feeding stimulatory effects of NE and MO (except in the DMN) and the feeding suppressive effects of NAL. Consistent with earlier reports, the PVN-cannulated animals exhibited a reliable increase in feeding after NE injection; the VMN cannula yielded a small feeding response, whereas the DMN and PFH were insensitive to NE. Morphine, in contrast, strongly stimulated eating after administration into PFH, as well as the PVN, apparently dissociating the NE and MO eating responses. The VMN, however, was generally unresponsive to both MO and NE. With regard to NAL's suppressive effect on feeding, the PVN and PFH, which were sensitive to MO, also exhibited responsiveness to opiate antagonism suggesting the existence in these areas of opiate receptors that modulate feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Norepinephrine, clonidine, and tricyclic antidepressants selectively stimulate carbohydrate ingestion through noradrenergic system of the paraventricular nucleus.

Using a self-selection feeding procedure, the present experiments examined the impact of central and peripheral injection of the alpha-adrenergic agonist clonidine (CLON) and the tricyclic antidepressant drugs amitriptyline (AMIT) and chlorimipramine (CIMIP) on nutrient selection in the adult male rat. In tests with mixed diets or with separate sources of the 3 macronutrients (carbohydrate, protein, and fat) simultaneously available, the following results were obtained: Peripheral and paraventricular nucleus (PVN) injection of CLON stimulated total food intake and preferentially increased ingestion of carbohydrate. Little or no change in protein or fat intake was observed. This pattern of response is similar to that observed with norepinephrine. PVN injection of AMIT and peripheral injection of CIMIP also selectively enhanced carbohydrate intake. These drug effects on carbohydrate selection occurred under a variety of conditions, including with mixed diets and pure dietary nutrients; under ad lib and restricted feeding conditions; in short (1 hr) as well as long (6 hr) test intervals; and in the absence or presence of a change in total calorie intake. Based on this and other evidence, it is proposed that noradrenergic neurons innervating the PVN in the rat play a role in regulating carbohydrate selection, and that this neurochemical system mediates the stimulating action of CLON and antidepressants on carbohydrate ingestion.

Amitriptyline↗
PubMed1985

Hypophysectomy disturbs the noradrenergic feeding system of the paraventricular nucleus.

Injection of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN) of satiated rats is known to stimulate eating behavior. In addition, drinking behavior is potentiated just prior to the onset of eating, followed by a strong inhibition of water intake. To understand the relationship between these PVN noradrenergic phenomena and endocrine processes associated with the PVN, chronically hypophysectomized animals were tested for their behavioral responsiveness to PVN NE injection. Pituitary ablation was found to abolish the NE-elicited eating response and the NE drinking suppressive effect. However, hypophysectomy had no impact on the NE-elicited preprandial drinking response, nor did it affect drinking produced by carbachol, angiotensin, and histamine, or the feeding and drinking responses induced by insulin. These results demonstrate that hypophysectomy disturbs PVN noradrenergic mechanisms in a behaviorally and pharmacologically specific specific manner.

Animals↗
PubMed1985

Feeding and drinking elicited by central injection of neuropeptide Y: evidence for a hypothalamic site(s) of action.

Neuropeptide Y (NPY), which exists in very high concentrations in the brain, has been shown to elicit a powerful feeding response and a small drinking response in satiated rats. In order to delineate the brain sites sensitive to these effects, NPY was injected through chronic guide cannulas into seven different brain regions, and the food and water intake of satiated rats was measured one hr postinjection. Injection of NPY (78 pmoles) into hypothalamic areas, namely the paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), and lateral hypothalamus (LH), elicited a strong feeding response; in contrast, injections into extra-hypothalamic areas, namely the amygdala, thalamus, and periaqueductal gray, were completely ineffective. Administration of NPY into the PVN and VMH also elicited a small drinking response; however, all other areas, including the LH, were insensitive to this effect. The findings that NPY was effective in the hypothalamus, as opposed to sites anterior, posterior, lateral or dorsal to this structure, suggest a hypothalamic site(s) of action for this neuropeptide.

Animals↗
PubMed1985

Noradrenergic innervation of the paraventricular nucleus: specific role in control of carbohydrate ingestion.

Acute injections of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN) have been shown to elicit eating in satiated rats. The present report examines the effects of acute and chronic PVN infusion of NE on intake of various liquid and mixed solid diets and on selection of the pure macronutrients, carbohydrate, protein, and fat. The results demonstrate that noradrenergic stimulation of the PVN (40 nmoles of NE) reliably enhances ingestion of pure sucrose diets (liquid and solid) and also of sweet and non-sweet milk solutions. Saccharin intake, in contrast, is unaffected. In preference tests, rats injected with NE show a greater increase in consumption of sucrose cubes compared with lab chow pellets, but exhibit an equivalent preference for sweet and non-sweet carbohydrate-rich diets. Tests with the three pure macronutrients simultaneously available reveal, after NE injection, a strong and selective increase in consumption of carbohydrate, with little or no change in intake of fat and, in some cases, a suppression of protein intake. This clear preference for carbohydrate can be seen with chronic NE infusion (5 nmoles every 30 min over a 14-day period), as well as after acute NE injection (40 nmoles), and also with long-term (24-hr) as well as short-term (1-hr) food intake measurements. This and other evidence suggests that the PVN noradrenergic system may play a specific and unique role in the control of carbohydrate ingestion.

Animals↗
PubMed1985

Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior.

Neuropeptide Y (NPY) was injected directly into the paraventricular nucleus of the hypothalamus (PVN) of satiated, brain-cannulated rats, and food and water intake were measured 0.5, 1, 2, 4, and 22 hr postinjection. NPY (24, 78, 235, 783, and 2351 pmol/0.3 mul) produced a large, dose-dependent increase in food intake as well as small increase in water intake. The latency to eat was about 10 min, with substantial feeding occurring in the first 30 min. At dose below 78 pmol, the eating generally occurred only within the first hour. At doses above 235 pmol, however, the subjects' food intake continued to increase such that by 4 hr postinjection they had consumed the equivalent of normal 22-hr intake, and 22 hr postinjection they had also eaten significantly more than control subjects. Previous studies have shown that norepinephrine injected into the PVN stimulates feeding through alpha-adrenergic receptors. To investigate a possible interaction, subjects were given PVN injections of phentolamine (60 nmol) prior to injections of either NPY (78 pmol) or norepinephrine (20 nmol). Phentolamine pretreatment significantly decreased feeding elicited by norepinephrine without affecting feeding elicited by NPY. This suggests that NPY does not stimulate feeding through the release of endogenous norepinephrine. The powerful stimulation of feeding elicited by this neuropeptide suggests an important role for hypothalamic NPY, or a structurally related peptide, in the regulation of feeding behavior.

Animals↗
PubMed1984

Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus.

Neuropeptide Y (NPY), a peptide contained within numerous presynaptic terminals in the hypothalamic paraventricular nucleus (PVN), was injected directly into the PVN of satiated, brain-cannulated rats, and food and water intake were measured 0.5, 1, 2 and 4 hrs postinjection. Neuropeptide Y (24 and 78 pmoles/0.3 microliter isotonic saline) caused a dose-dependent increase in food intake, as well as a small, dose-dependent increase in water intake. This effect on feeding occurred even when food was not presented until 4 hrs postinjection. To determine the behavioral specificity of this effect, the impact of PVN injection of NPY (78 pmoles) on various behaviors was observed. With food available, only feeding and drinking behavior were affected. No change in other behaviors, including grooming, rearing, sleeping, resting or different levels of activity, was observed. With food absent, NPY still elicited drinking, suggesting that this is a primary effect, rather than secondary to the feeding. In addition to drinking, NPY reliably increased activity while decreasing sleep and grooming. These results suggest an important role for hypothalamic NPY, or a structurally-related peptide, in the regulation of feeding and drinking behavior.

Animals↗
PubMed1984

Determination of the course of brainstem catecholamine fibers mediating amphetamine anorexia.

Previous studies suggest that brainstem catecholamine (CA) fibers which mediate amphetamine (AMPH)-induced anorexia ascend through the midlateral medical forebrain bundle and perifornical region and terminate in the perifornical hypothalamic region (PFH) at the level of the hypothalamic ventromedial nucleus. Through studies of wire-knife cuts (KCs) placed in the lower brainstem, the present paper further delineates the course of fibers mediating AMPH feeding suppression, as they ascend through the medullary, pontine and midbrain tegmentum. The results indicate that the crucial CA fibers ascend through the ventrolateral medulla just dorsal to the nucleus of the seventh cranial nerve, 1.1-1.9 mm lateral to midline. In their rostral course, these fibers apparently maintain a relatively straight position in the ventral pons and then enter the ventrolateral midbrain just dorsal to the medial lemniscus, between 0.7 and 1.1 mm lateral to midline. These medullary fibers, possibly originating from the norepinephrine/epinephrine-containing ventrolateral cell group (A1/C1), then appear to join additional fibers from the scattered dopamine-containing neurons positioned in the caudal midbrain (A8 CA cell group). Together, these dopamine, epinephrine and norepinephrine systems are believed to ascend into the medial aspect of the medial forebrain bundle on their way to the PFH at the level of the ventromedial nucleus.

Afferent Pathways↗
PubMed1984

Clonidine-induced feeding: analysis of central sites of action and fiber projections mediating this response.

Clonidine (CLON), an alpha-adrenergic agonist, was used in conjunction with norepinephrine (NE) to elicit feeding in satiated rats that had sustained hypothalamic electrolytic lesions, or coronal knife cuts at the hypothalamic, midbrain or pontine level of the brainstem. Electrolytic lesions of the paraventricular nucleus (PVN) of the hypothalamus significantly attenuated feeding normally stimulated by intraperitoneal injection of CLON. This contrasts with lesions in the dorsomedial or perifornical hypothalamic regions which had no effect on CLON-elicited eating. Knife cuts placed in the posterior hypothalamus and throughout the midbrain tegmentum also left intact the CLON eating response, in contrast to specific cuts in the dorsal pontine tegmentum which disrupted feeding elicited by PVN injections of NE and CLON, as well as by peripheral administration of CLON. Analyzed together, these results with effective and ineffective cuts relative to CLON and NE feeding provide evidence for an alpha-adrenergic feeding circuit which originates in the PVN and descends from this nucleus, via a dorsal periventricular course, through the diencephalon and midbrain. Further caudally, these fibers mediating NE and CLON feeding then appear to traverse ventrolaterally into the dorsolateral pontine tegmentum on their way to the dorsal medulla.

Animals↗
PubMed1984

Noradrenergic feeding elicited via the paraventricular nucleus is dependent upon circulating corticosterone.

Feeding behavior elicited by injection of norepinephrine (NE) into the paraventricular nucleus (PVN) of satiated rats has been shown to be abolished by hypophysectomy. To determine the specific nature of this dependence of NE's action on pituitary hormones, the efficacy of PVN-injected NE was examined in rats subjected to hypophysectomy, as well as to adrenalectomy, thyroidectomy, and gonadectomy, and also in operated rats receiving hormone replacement therapy. The feeding response induced by NE was almost completely abolished in adrenalectomized as well as hypophysectomized animals, but remained unimpaired after thyroidectomy and gonadectomy. The NE response was significantly restored in hypophysectomized rats by daily subcutaneous injections of corticosterone, but not by thyroxine, testosterone, insulin, or the mineralocorticoid deoxycorticosterone. In adrenalectomized rats, subcutaneous corticosterone implants as well as daily corticosterone injections (as opposed to deoxycorticosterone injections) effectively restored the NE eating effect. Radioimmunoassay of plasma corticosterone indicated that the level of hormone was positively correlated with the strength of the animals' response to the NE injection. These findings demonstrate that the loss of response to NE subsequent to hypophysectomy is due to a disruption of the hypothalamo-pituitary-adrenal axis. The glucocorticoids of the adrenal gland appear to be the essential humoral factor interacting permissively with PVN-injected NE to elicit feeding.

Animals↗
PubMed1984

Chronic infusion of norepinephrine and clonidine into the hypothalamic paraventricular nucleus.

Previous experiments have shown that acute injection of NE and CLON into the PVN initiates a short-term feeding response in satiated rats. This study examined, in brain-cannulated rats, the impact of remote, chronic injections of NE, CLON, or saline on daily food intake and body weight gain. Over a period of 14 days, NE was infused into the PVN, either continuously at a rate of 12 nm/microliter/hr, or discretely at a rate of 6 nm/microliter/sec. In addition, the alpha 2-adrenergic agonist CLON was infused into the PVN discretely at a rate of 3 nm/0.5 microliter/30 sec. Relative to saline infusion, chronic (continuous or discrete) stimulation of the PVN with either of these drugs was effective in potentiating daily food intake by 12-19% and in increasing body weight gain, from approximately 1.5 g/day to 3.3 g/day. This evidence indicates that medial hypothalamic NE, especially within the PVN, is sufficiently robust to alter long-term feeding patterns and body weight regulation.

Animals↗