Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracisternal (IC) injection of the GABA-transaminase inhibitor, ethanolamine-O-sulfate (EOS), has been previously shown to induce dose-dependent anorexia in normal rats as well as to reverse overeating in several rodent models of acute and chronic hyperphagia. To determine if such anorexia might be mediated by cells within or fibers of passage which traverse the lateral hypothalamus (LH), adult female rats received bilateral radiofrequency heat lesions of the LH vs. anesthesia control injections and were allowed to recover normal feeding and drinking responses. Using a longitudinal design, all animals then received 100, 0, and 200 micrograms EOS in 20 microliters deionized water IC with 1 week separating each injection. In addition to daily measures of feeding, drinking and body weight, all animals were screened 24 hr after injections for sensorimotor competence and general health by testing open-field activity, catalepsy, paw-lick responses on a hot-plate and rectal temperature. As reported previously, IC EOS induced dose-dependent hypophagia and weight loss. However, the magnitude and duration of these effects were equivalent in lesioned and control rats. In addition, open-field activity and body temperature were reliably lowered as a function of dosage while catalepsy was increased. Again, this effect was equivalent in lesioned and control rats. Subsequent tests of drinking and feeding in response to hyperosmotic and hypoglycemic challenges, respectively, confirmed that lesioned rats were deficient compared to controls. These findings suggest that an intact LH axis is not required for the anorexigenic effects of IC EOS.
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PMID:Effects of lateral hypothalamic lesions on the anorexia induced by ethanolamine-O-sulfate. 273 38

Nondeprived male rats were familiarized with 30 min daily access to a highly palatable diet. Clonazepam, midazolam and chlordiazepoxide each produced significant dose-dependent increases in food consumption. Clonazepam was the most potent, and a significant hyperphagic effect was detected following 0.078 mg/kg (IP). Amongst novel non-benzodiazepine anxiolytics, zopiclone and CL 218,872 also produced significant increases in food intake. The smallest doses to produce significant hyperphagia for these two drugs were 10.0 and 2.5 mg/kg (IP) respectively. In contrast, tracazolate caused only a reduction in feeding, evident at 20 and 40 mg/kg (IP). Previous reports indicate that although benzodiazepines, zopiclone and CL 218,872 displace [3H] flunitrazepam binding in rat cerebral cortex preparations, tracazolate enhances the binding. Our results are consistent with the drug-induced hyperphagia depending upon agonist actions at high-affinity benzodiazepine sites. They also provide pharmacological evidence for a dissociation between hyperphagic and anxiolytic drug effects. Phenobarbital (2.5-40.0 mg/kg), like the benzodiazepines, produced a strong stimulation of food intake, indicating that drug action at an alternative site in the benzodiazepine receptor-GABA receptor-chloride channel complex can also lead to hyperphagia.
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PMID:Benzodiazepine-induced hyperphagia in the nondeprived rat: comparisons with CL 218,872, zopiclone, tracazolate and phenobarbital. 286 47

Nondeprived male rats were familiarised with daily 60 min access to a highly palatable diet, consisting of powdered rat diet, sweetened condensed milk and water. Clonazepam (0.625-5.0 mg/kg, IP) produced a substantial increase in food consumption within the first 30 min of access. The increase was similar across all dose conditions, suggesting that a maximal effect may have been achieved with a dose as small as 0.625 mg/kg. The hyperphagia induced by clonazepam was reversed by the benzodiazepine receptor antagonist, Ro15-1788 (5.0-20.0 mg/kg), indicating that the effect was benzodiazepine receptor-mediated. Treatments with the peripheral-type benzodiazepine agonist, Ro5-4864, did not induce a hyperphagic response. Instead, food consumption was significantly depressed following the administration of Ro5-4864 at 20 and 40 mg/kg, IP. A comparison of the clonazepam and Ro5-4864 data suggests that benzodiazepine-induced hyperphagia is mediated by central-type benzodiazepine binding sites. The pyrazoloquinoline, CGS 9896, binds with high affinity to benzodiazepine sites and has recently been described as a nonsedating anxiolytic. CGS 9896 (2.5-20.0 mg/kg, administered either IP or PO) did not affect consumption of the highly palatable diet. In consequence, anxiolytic and hyperphagic effects of drug actions at benzodiazepine receptors may be dissociated in the case of this compound. The atypical 1,4-benzodiazepine, Ro5-3663, a GABA antagonist which may act at the picrotoxinin site, produced a dose-related reduction in food consumption. Comparison with the results for Ro5-4864 rules out an interpretation for the anorexia in terms of anxiogenic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clonazepam-induced hyperphagia in nondeprived rats: tests of pharmacological specificity with Ro5-4864, Ro5-3663, Ro15-1788 and CGS 9896. 298 43

The effect of GABA antagonists picrotoxin and bicuculline was studied on hyperphagia caused by 2-DG and 5-TG. The GABA antagonists were administered either SC or into the VMH or LH through stereotaxically implanted chronic cannulae. The peripheral as well as VMH injection antagonised the hyperphagia significantly. In contrast, injection of these agents into the LH failed to produce any effect. These findings show that in a glucoprivic state there might be an increased GABAergic activity in the VMH.
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PMID:Antagonism of acute feeding response to 2-deoxyglucose and 5-thioglucose by GABA antagonists: the relative role of ventromedial and lateral hypothalamus. 374 38

The effects of GABA antagonists, picrotoxin and bicuculline were studied on hyperphagia caused by insulin in free feeding rats. It was found that peripheral administration of GABA antagonists inhibited this hyperphagia. These agents were administered in the VMH and LH through stereotaxically implanted cannulae. It was found that the food intake was inhibited when injected into the VMH, but not in the LH. These findings suggest that LH plays a relatively passive role as compared to VMH, where GABA appears to be an important neurotransmitter.
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PMID:Inhibition of insulin hyperphagia by gamma aminobutyric acid antagonists in rats. 637 50

Because of the evidence that benzodiazepine binding sites are associated with GABA receptors in the central nervous system, it has been suggested that the behavioural effects of benzodiazepines may be mediated by GABAergic mechanisms. In order to investigate this hypothesis in relation to the hyperphagia produced by benzodiazepines, the effects of chlordiazepoxide were compared with those of the GABA agonists progabide and muscimol and the GABA antagonists picrotoxin and bicuculline. In rats adapted to a 22 h/day food deprivation schedule chlordiazepoxide produced a dose-related increase in food intake. Neither progabide nor muscimol produced a similar effect after IP injection, nor did these drugs potentiate the effects of a dose of chlordiazepoxide. Picrotoxin and bicuculline, each given at a sub-convulsant dose, did not affect quantities of food consumed and also did not antagonise the effect of chlordiazepoxide. These results provide no evidence for the hypothesis that chlordiazepoxide-induced hyperphagia in rats is mediated by GABAergic mechanisms.
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PMID:Chlordiazepoxide-induced hyperphagia in rats: lack of effect of GABA agonists and antagonists. 644 Jan 85

Past literature is reviewed briefly which suggests that variations in brain GABA metabolism may be involved in the control of food intake in rats. Recent experiments from the author's laboratory are summarized in which brain GABA has been elevated in adult female rats by intracisternal injection of the GABA-transaminase inhibitor, ethanolamine-O-sulfate (EOS). Central EOS pretreatment produced dose-dependent anorexia in normal subjects and prevented acute overeating in response to systemic insulin (12 U/kg) or 2-deoxyglucose (750 mg/kg). Similar EOS pretreatment essentially reversed the chronic overeating induced by diet palatability, bilateral medial hypothalamic lesions or genetic predisposition (in Zucker fatty rats). The ubiquity of these anorexic effects in the absence of clear motor debilitation suggests that drugs which elevate brain GABA deserve further investigation for their potential utility in the clinical treatment of overeating.
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PMID:GABA and feeding: reversal of overeating by central GABA-transaminase inhibition. 668 89

Acute feeding responses to 2-deoxyglucose (750 mg/kg) or insulin (12 U/kg) were examined 24 hr after intracisternal injection of the GABA-transaminase inhibitor ethanolamine-O-sulfate (EOS, 400 micrograms) in female rats. EOS pretreatment completely abolished acute feeding responses to both challenges. These findings complement recent research showing that central EOS can reverse chronic overeating in several experimental preparations. The present results are consistent with previous indications that EOS treatment may induce a metabolic shift away from brain glucose utilization, thus making glucoprivation irrelevant as a metabolic challenge. An alternative possibility is that EOS-induced increases of brain GABA may offset specific neural mechanisms through which these glucoprivic agents normally induce feeding.
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PMID:Inhibition of acute feeding responses to systemic 2-deoxyglucose or insulin in rats pretreated with the GABA-transaminase blocker ethanolamine-O-sulfate (EOS). 676 11

The hypothesis that benzodiazepine-induced hyperphagia is due to a specific enhancement of the palatability of foods has been supported by previous 'taste reactivity' studies of affective (hedonic and aversive) reactions to taste palatability. Diazepam and chlordiazepoxide enhance hedonic reactions of rats (rhythmic tongue protrusions, etc.) to sweet tastes in a receptor-specific fashion. A role for brainstem circuits has been indicated by a previous demonstration of the persistence of the taste reactivity enhancement by diazepam after midbrain decerebration. The present study examined whether benzodiazepine brainstem receptors are the chief substrates for palatability enhancement even in intact brains. We compared the effectiveness of benzodiazepine microinjections to elicit feeding and enhance hedonic reactions when delivered into either the lateral ventricle (forebrain) or the fourth ventricle (brainstem) of rats. The results show diazepam is reliably more effective at eliciting feeding and enhancing positive hedonic reactions to oral sucrose when microinjections are made in the fourth ventricle than in the lateral ventricle. We conclude that brainstem neural systems containing benzodiazepine-GABA receptors are likely to be the chief substrates for benzodiazepine-induced palatability enhancement.
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PMID:Brainstem mediates diazepam enhancement of palatability and feeding: microinjections into fourth ventricle versus lateral ventricle. 884 79

The present studies were undertaken to investigate the neuroactive steroidal modulation of feeding behavior and possible involvement of gamma-aminobutyric acid type-A (GABA-A) and mitochondrial diazepam binding inhibitor (DBI) receptors (MDR) in food-deprived male mice. Allopregnanolone (0.5-2 mg/kg), a neurosteroid, progesterone (1-10 mg/kg), a neurosteroid precursor, and 4'-chlordiazepam (0.25-1 mg/kg), a specific high affinity MDR agonist, produced a dose-dependent hyperphagic effects. In contrast, neurosteroids pregnenolone sulfate (PS) (1-10 mg/kg) and dehydroepiandrosterone sulfate (DHEAS) (1-10 mg/kg) produced a hypophagic effect, in a dose-dependent manner. The allopregnanolone-, progesterone- and 4'-chlordiazepam-induced hyperphagic effect was blocked by picrotoxin (1 mg/kg), a GABA-A chloride channel antagonist, but not by flumazenil (2 mg/kg), a benzodiazepine (BZD) antagonist. The 4'-chlordiazepam-induced hyperphagic effect was prevented by pretreatment with PK11195 (2 mg/kg), a selective partial MDR antagonist. The hypophagic effect of DHEAS (10 mg/kg) was reversed by dizocilpine (10 microg/kg), an NMDA receptor antagonist, but resistant to muscimol (0.1 mg/kg), a selective GABA-A receptor agonist. In contrast, the PS (10 mg/kg)-induced hypophagic response was resistant to dizocilpine, but sensitive to muscimol (0.1 mg/kg). Both the sulfated neurosteroids PS and DHEAS also reversed the hyperphagic effect of allopregnanolone. In addition, the BZD agonist triazolam (0.05-0.25 mg/kg) also produced a flumazenil- and picrotoxin-sensitive hyperphagic effects, thereby suggesting the changes in feeding behavior by neurosteroids represent GABA-A receptor mediated hyperphagic action. Although the possible antistress or anxiolytic actions of neurosteroids may confound the hyperphagia, behavioral effects observed were specific to food because the mice were adopted to the test environment and diet, and of a possible variation between various neurosteroids in the extent to which antistress or anxiolytic effect produced at hyperphagic doses. The hyperphagic effects of progesterone and 4'-chlordiazepam resembled that of neurosteroid allopregnanolone. Therefore, the effect of progesterone may be imputed to its metabolism to allopregnanolone, while the 4'-chlordiazepam-induced hyperphagic response is related to its MDR-stimulated neurosteroidogenesis and subsequent modulation of GABA-A receptors. The hypophagic response following DHEAS may, at least partly, involve an NMDA receptor mechanism. However, PS-induced hypophagia may be mediated by GABA-A or other receptor systems. These data suggest a pivotal role for GABA-A and mitochondrial DBI receptors in the hyperphagic effects of neurosteroids and reinforces a role for endogenous neurosteroids in regulating feeding behavior. Future studies may lead to the development of neurosteroid-based anorectic/hyperphagic agents for therapeutic use.
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PMID:The role of GABA-A and mitochondrial diazepam-binding inhibitor receptors on the effects of neurosteroids on food intake in mice. 967


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