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Biomedical subjects

S F Leibowitz

Publications and source records attributed to S F Leibowitz.

At least 145 records · Page 8Linked to original sources
PubMed1984

Chronic norepinephrine injection into the hypothalamic paraventricular nucleus produces hyperphagia and increased body weight in the rat.

A single injection of norepinephrine (NE) into the paraventricular nucleus (PVN) is known to elicit a feeding response in the satiated rat. Through repeated NE injections, the present study set out to determine whether chronic noradrenergic stimulation of the PVN is effective in producing changes in total daily food intake, as well as in body weight gain. The results indicate that repeated injections of NE (20 nmoles/injection given 4 times/day) cause a stimulation of eating with each injection and consequently produce a significant increase in total daily food intake. This stimulatory effect on feeding behavior occurs under food-restricted conditions, where food is available only at times (in the daytime) when NE is injected, and also under food-satiated conditions were food is available essentially ad lib. This hyperphagia results in a gradual increase in body weight which develops over the course of a 5-day sequence of repeated NE injections. There is some evidence to suggest that the overeating produced by NE throughout the day may be attributed specifically to an increase in meal size rather than to a change in meal frequency. This evidence suggests that medial hypothalamic NE, particularly within the PVN, may play a role in long-term feeding behavior and body weight regulation.

Animals↗
PubMed1984

Feeding behavior after hypothalamic 6-hydroxydopamine injections.

6-Hydroxydopamine (6-OHDA) injection into the rat hypothalamus produces profound changes in eating behavior and body weight gain. Willis and Smith have demonstrated an anorexic effect of lateral hypothalamic (LH) 6-OHDA, which they correlate with local catecholamine release from degenerating axons just behind the lesion. Work from our own laboratory has recently demonstrated that 6-OHDA injection into the medial paraventricular nucleus (PVN) has an initial effect of stimulating daily food intake and body weight gain. It is suggested that this phenomenon, consistent with reports of enhanced eating with PVN injection of norepinephrine (NE), is due to 6-OHDA-induced release of endogenous NE. Subsequently, PVN 6-OHDA causes hypophagia and reduced body weight. Although histochemical and biochemical analyses reveal a 60-90% decrease in PVN norepinephrine and dopamine after 6-OHDA treatment, a close association between the precise degree of catecholamine loss and magnitude of behavioral response could not be detected.

Animals↗
PubMed1983

Feeding behavior induced by central norepinephrine injection is attenuated by discrete lesions in the hypothalamic paraventricular nucleus.

Extensive brain-cannula mapping studies in the rat have demonstrated that the hypothalamic paraventricular nucleus (PVN) is the most sensitive brain site for eliciting eating behavior with central norepinephrine (NE) injection. The present experiments examined the impact of lesions aimed at the PVN on this NE-elicited eating response. In rats with NE injection cannulas aimed at the lateral ventricle, bilateral lesions of the PVN significantly attenuated, by 60 to 70%, the eating effect induced by NE, at doses ranging from 20 to 160 nmoles. PVN lesions which extended ventrally to damage tissue lying within the periventricular region were more effective in abolishing the NE response than were lesions that remained confined to the dorsal aspects of the PVN. Large lesions located just dorsal to the PVN had no impact on the NE response. This evidence supports the primary role of the PVN in mediating the eating behavior elicited by central noradrenergic activation.

Animals↗
PubMed1983

Relationship of adrenergic and electrical brain stimulation induced feeding responses.

Electrical and adrenergic brain stimulation can induce eating in satiated animals. This report explores the interrelationship of brain feeding systems mediating eating in response to norepinephrine and electrical stimulation of the hypothalamus in rats. It was found that simultaneous adrenergic and electrical brain stimulation resulted in a significant increase in food intake as compared to each stimulation condition alone. Furthermore, pharmacological blockade of the alpha-adrenergic receptors in the hypothalamus attenuated feeding in response to adrenergic, but not electrical brain stimulation. Results are interpreted to suggest that these feeding systems are independent at the level of the diencephalon. The role of the vagus nerve as an efferent link through which these brain systems may influence feeding behavior is discussed.

Animals↗
PubMed1982

Effects of hypothalamic knife cuts on feeding induced by paraventricular norepinephrine injections.

The relationship between the fiber systems involved in the hypothalamic noradrenergic feeding response and the medial hypothalamic (MH) hyperphagia syndrome was appraised in male rats using knife cuts. Parasagittal knife cuts in the perifornical hypothalamus produced hyperphagia and excessive weight gain but failed to disrupt feeding in response to paraventricular hypothalamic injections of norepinephrine (NE). Coronal knife cuts in the posterior hypothalamus which extended from the midline to the lateral perifornical region also failed to disrupt NE feeding. These findings indicate that the output of the noradrenergic feeding system does not follow the feeding pathway implicated in the MH hyperphagia syndrome. They also suggest that the output of the noradrenergic feeding system is not directed laterally beyond the level of the fornix nor caudally into the lower brainstem over the medial forebrain bundle.

Animals↗
PubMed1981

Evidence for vagal involvement in the eating elicited by adrenergic stimulation of the paraventricular nucleus.

We examined the role of the vagus nerves in mediating the eating and preprandial drinking seen after injection of norepinephrine (NE) into the region of the paraventricular hypothalamic nucleus of satiated rats. Complete subdiaphragmatic vagotomy (confirmed by gastric secretion tests) abolished the NE-elicited eating response, whether the diet used was lab chow, milk, or a milk-chow misture, and attenuated, by 38%, the NE-elicited drinking response. These effects occurred independently of changes in body weight or daily food intake imposed by vagal surgery. The vagotomized rats retained the capacity to rapidly increase eating in response to food deprivation or insulin injection challenges, indicating that the effect of vagotomy on NE-induced eating was not due to some non-specific impairment. Efferent vagal blockade of intact rats with systemic injections of atropine methyl nitrate (0.4 mg/kg) prior to central NE infusions yielded similar results. Finally-selective section of the coeliac branch of the vagus produced a 49% reduction of NE, elicited eating, as compared with a 29% reduction in water intake, while selective section of the gastric plus hepatic vagal branches, leaving only the coeliac branch intact, did not significantly affect either ingestive response. Both of these selectively vagotomized groups displayed an unimpaired capacity to increase food intake in response to systemic insulin injections. These results suggest participation of efferent vagal mechanisms in the adrenergic feeding, and, to a lesser extent, drinking phenomena and are consistent with a particular role for some function under coeliac vagal control (perhaps insulin secretion) in modulating the effects of NE on feeding behavior.

Animals↗
PubMed1981

L-Tryptophan's effects on mouse killing, feeding, drinking, locomotion, and brain serotonin.

Injections of the serotonin precursor l-tryptophan (25, 50, and 100 mg/kg IP), inhibited mouse killing behavior in rats, as indicated by a dose dependent increase in latencies to attack and kill mice. Tests in 24 hr food deprived rats revealed that feeding behavior was also significantly decreased by about 30% by tryptophan injections (50--100 mg/kg IP). Concomitant with the behavioral changes were increased levels of brain serotonin and its metabolite 5-hydroxyindoleacetic acid. Drinking, latencies to sniff mice, and ability to locomote on a rotating rod were not affected by l-tryptophan injections, although spontaneous activity in an open field was reliably reduced by 33% with a dose of 100 mg/kg. Thus, while the degree of selectivity for tryptophan's effects on behavior remains open to question, these findings are consistent with hypotheses of an inhibitory role for central serotonergic systems, particularly in mouse killing and feeding behaviors.

Aggression↗
PubMed1980

Histochemical and pharmacological analysis of noradrenergic projections to the paraventricular hypothalamus in relation to feeding stimulation.

Three techniques, namely, midbrain lesions, fluorescence histochemistry, and brain cannulation, were used in combination to analyze noradrenergic projections to the paraventricular nucleus of the hypothalamus (PVN) and their function in stimulating feeding behavior. The convergence of evidence indicates that the dorsal component of the central tegmental tract (CTT), which ascends through the dorsal pons and then projects through the medial tegmental radiations (TR) into the ventral tegmentum just dorsal to the media lemniscus, contains the crucial noradrenergic axons which innervate the PVN and mediate noradrenergic stimulation of feeding behavior. The primary evidence for this conclusion is that dorsal tegmental electrolytic or 6-OHDA lesions which damaged specifically these fibers invariably caused: (1) a reduction of catecholamine varicosities within the PVN (most notably, fine and moderate-size, rounded varicosities within the parvocellular area); (2) a strong reduction or loss of the feeding response elicited by PVN injection of the presynaptically-acting drugs tranylcypromine and desipramine; and (3) a potentiation of the same response produced by injected norepinephrine. These pharmacological and neurochemical changes in the PVN were reduced in magnitude if the dorsal CTT and medial TR fibers received only partial damage, and these changes did not occur at all if the lesion fell immediately dorsal to these fibers without damaging them. Specific lesions in the ventral tegmentum, which also failed to damage the dorsal CTT and TR axons but instead damaged the ventral component of the CTT, not only failed to disrupt the action of the antidepressant agents but actually potentiated their effectiveness in the PVN. Ventromedial lesions, however, which severed the rostroventral extension of the dorsal CTT and medial TR fibers, had the same behavioral consequences as had the dorsal lesions which damaged this projection at a more dorsocaudal level. Finally, damage to other catecholamine projections had little effect on PVN function in stimulating eating.

Adrenergic Fibers↗
PubMed1980

Histochemical and pharmacological analysis of catecholaminergic projections to the perifornical hypothalamus in relation to feeding inhibition.

Three techniques, namely, midbrain lesions, fluorescence histochemistry and brain cannulation, were used in combination to analyze catecholamine (CA) projections to the perifornical hypothalamus and their function in suppressing feeding behavior. The convergence of evidence indicates that the ventral adrenergic component of the central tegmental tract and dopaminergic projections from midbrain A8 and possibly A9 cell groups contain the crucial fibers which innervate the perifornical hypothalamus and mediate CA suppression of feeding behavior. The primary evidence for this conclusion is that ventral tegmental electrolytic or 6-OHDA lesions which damaged specifically these fibers invariably caused: (1) a marked reduction of CA varicosities in the perifornical area; (2) a strong reduction or loss of the anorectic response produced by perifornical injection of the presynaptically acting drugs amphetamine and mazindol; and (3) a potentiation of the anorectic response produced by perifornical injection of the CA receptor agonists dopamine and epinephrine. Lesions in the dorsal midbrain tegmentum, which left intact the ventral adrenergic and dopaminergic fibers but damaged the compact dorsal tegmental bundle, the dorsal fibers of the central tegmental tract and the medial and lateral tegmental CA radiations, had no apparent effect on the responsiveness of the perifornical hypothalamus to CA drug stimulation, as well as on the CA fluorescence in that region. Lesions in the area of the dopaminergic A10 cells and the midline tegmental CA radiations actually potentiated the effectiveness of the anorexigenic drugs in the perifornical hypothalamus.

Adrenergic Fibers↗
PubMed1979

Mapping study of brain dopamine- and epinephrine-sensitive sites which cause feeding suppression in the rat.

Central injections of dopamine (DA) or epinephrine (EPI) have been found to suppress feeding behavior in hungry rats. In the present study, 24 different brain areas, in 299 animals, were examined to localize the precise region of catecholamine (CA) sensitivity. Essentially all sites outside the hypothalamus, as well as in the medial portion of the hypothalamus, were relatively or totally unresponsive to DA or EPI. The area of greatest sensitivity for both agonists (where they yielded a 50--70% suppression of feeding) was found to be the perifornical region of the lateral hypothalamus, extending from the caudal aspect of the paraventricular nucleus to the caudal aspect of the ventromedial nucleus. Dorsal, lateral, or ventrolateral movement of the injection site away from the fornix and into the zona incerta or the lateral hypothalamic medial forebrain bundle area caused a dramatic reduction in the effectiveness of the CA. These findings are consistent with histochemical studies, which have shown the fornix to be surrounded by CA varicosities, and pharmacological studies, which have shown the perifornical region to be most sensitive to the anorexic effect of centrally injected amphetamine, which releases endogenous CA. It is suggested that the perifornical hypothalamus plays a role in the process of inhibiting food consumption in response to increased dopaminergic and adrenergic activity.

Amphetamine↗
PubMed1979

Pharmacological characterization of perifornical hypothalamic dopamine receptors mediating feeding inhibition in the rat.

Mapping studies with central drug injections in the hungry rat have identified the perifornical lateral hypothalamus as being uniquely sensitive to the feeding suppressive effects of exogenous dopamine, as well as anorexic drugs which release endogenous catecholamines. In the present study, the hypothalamic dopamine-receptive sites mediating this phenomenon were pharmacologically characterized. These sites, studied via direct drug injection into the perifornical hypothalamus of freely moving, brain-cannulated rats, were found to be most responsive to dopamine, in a dose-dependent manner, but were also activated by other catecholamine receptor stimulants, with the order of potency being dopamine greater than apomorphine = epinine greater than norepinephrine. Clinically effective neuroleptic compounds antagonized these dopamine-sensitive sites, apparently in a competitive and stereochemically specific manner. The relative potency of the neuroleptics and structurally related compounds was calculated to be haloperidol greater than fluphenazine greater than chlorpromazine greater than pimozide greater than promazine. The ineffective neuroleptic promethazine, the tricyclic antidepressants imipramine and desipramine, and the antagonists of alpha-adrenergic, beta-adrenergic, cholinergic, and serotonergic receptors, did not manifest the ability to reverse dopamine's action. These results thus reveal properties of these hypothalamic dopamine-sensitive, feeding inhibitory sites which match to a large extent the characteristics recently identified for dopamine receptors in the periphery and extrahypothalamic brain areas.

Adrenergic alpha-Antagonists↗
PubMed1979

Manipulations of dietary tryptophan: effects on mouse killing and brain serotonin in the rat.

Maintaining rats on a tryptophan-free diet for 4--6 days induced mouse killing in non-killer rats, and significantly facilitated killing in killer rats, as indicated by shorter latencies to kill the mice. The killing responses were similar in topography to the natural killing responses. These changes in killing behavior did not appear to be due to generalized changes in irritability. The increased killing after maintenance on a tryptophan-free diet was accompanied by a 26% reduction in brain serotonin (5-HT) and a 29% reduction in brain 5-hydroxyindoleacetic acid (5-HIAA). When the tryptophan-free diet was supplemented with L-tryptophan (0.5 or 2%), brain 5-HT and 5-HIAA were increased above control levels, and the rat's killing response appeared normal both in terms of latency and topography, similar to that seen in control chow fed animals. While rats consumed less of the tryptophan-free and tryptophan supplemented diets, control subjects deprived of chow such that they lost as much weight as rats fed the tryptophan-free diet, did not show changes in killing behavior. These results are consistent with the hypothesis that central serotonergic systems exert inhibitory control over mouse killing behavior in rats.

Aggression↗
PubMed1979

L-Dopa feeding suppression: effect on catecholamine neurons of the perifornical lateral hypothalamus.

Injection of L-Dopa (0.8--200 nmoles) into the perifornical hypothalamus produced a dose-dependent suppression of feeding in hungry rats. This effect was positively correlated in magnitude with the same effect produced by the catecholamine agonists dopamine and epinephrine, and by the catecholamine-releasing drug amphetamine. L-Dopa's action was partially antagonized by separate injections of the dopaminergic blocker haloperidol (58% blockade) and the beta-adrenergic blocker propranolol (38% blockade). Combined injections of these two antagonists produced a 90% blockade of L-Dopa's effect. Perifornical administration of the dopa decarboxylase inhibitors Ro 4-4602 and MK-486 was also shown to reverse L-Dopas feeding suppression, at doses that enhanced the effect of injected dopamine and epinephrine. On the basis of these findings, L-Dopa appears to suppress food consumption in part through increased catecholamine synthesis, specifically within dopaminergic and adrenergic neurons of the perifornical hypothalamic region.

Animals↗