Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003123 (anorexia)
 13,794 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurochemical mechanisms by which drugs acting on central serotoninergic system modify feeding were reviewed. Fenfluramine, a clinically effective appetite suppressant, releases serotonin from nerve terminals and inhibits its reuptake, and considerable evidence suggests that these effects mediate its anorectic activity. The D isomer of fenfluramine is particularly specific in affecting serotonin mechanisms and causing anorexia. Transmitters other than serotonin such as acetylcholine, catecholamines and GABA are also affected by systemic administration of fenfluramine, but some of these effects are secondary to fenfluramine's action on serotoninergic mechanisms. Moreover, there is no evidence that these brain substances are involved in fenfluramine's ability to cause anorexia. Several studies with drugs affecting different serotonin mechanisms such as release and uptake or mimicking the action of serotonin at post-synaptic receptors suggest that increase serotonin release and direct stimulation of postsynaptic receptors are the most effective mechanisms for causing depression of food intake, although inhibition of serotonin uptake may also contribute in appropriate conditions. Development of serotonin receptor hyposensitivity and, in some instances, decreased serotonin levels may lead to tolerance to the anorectic activity of drugs enhancing serotonin transmission, the degree of this depending critically on the type of effect on serotonin mechanisms and intensity and duration of serotonin receptor activation. Recent evidence suggests that a decrease in serotonin function causes stimulation of feeding. This may lead to development of new strategies for the treatment of clinical anorexias.
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PMID:Neurochemical mechanism of action of drugs which modify feeding via the serotoninergic system. 242 23

1. Baclofen given intraperitoneally (i.p.) to rats caused a dose-dependent decrease in food intake. 2. Bicuculline or picrotoxin (GABAA-antagonist) and methergoline (5-HT antagonist) decreased the anorectic effect of baclofen. 3. Pimozide (dopamine receptor blocker), phenoxybenzamine and propranolol (alpha and beta adrenergic blockers) did not diminish the baclofen effect, but even increased the anorexia induced by the drug. 4. It can be postulated that, at least partially, GABAA receptor mechanism, GABA-5HT receptor complex and/or 5-HT mechanism may be involved in baclofen induced anorexia.
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PMID:Food intake suppressant effect of baclofen in rats. 260 37

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

The importance of the central monoamines NE, DA and 5-HT in ingestive behavior has inevitably resulted in considerable effort being expended in attempting to implicate these monoamines in the mechanism of action of anorectic drugs. The statements that amphetamine-induced anorexia is unlikely to be due to central serotoninergic systems and that central noradrenergic and dopaminergic systems are not implicated in the appetite suppressant effect of fenfluramine are in all probability correct. However, to attribute the ability of drugs to decrease food intake unequivocally to a specific effect on central monoaminergic systems is almost certainly an oversimplification, due to the fact that other putative neurotransmitters, such as GABA and peptides, play a critical role in eating. This can be achieved either directly or by modulating the release of other transmitters. An added complication in attempting to correlate a specific neurochemical process to a behavioral effect, such as anorexia, is the complexity of the central actions of the drug. At best, a predominant but not an exclusive process can be identified. Perhaps the in-built constraint of attempting to correlate a specific neurochemical effect to the desired action of a drug is accountable for the absence of a second generation of centrally acting anorectic drugs. Dramatic progress has been made in elucidating the factors involved in ingestive behavior over the last 5-10 years. This information should, and must, provide the catalyst for more efficacious anorectic drugs because obesity represents one of the few major diseases for which adequate drug therapy does not exist.
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PMID:Neuropharmacology of drugs affecting food intake. 288 62

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 therapeutic efficacy and safety of oxiracetam (ISF 2522), a new nootropic cyclic GABA derivative, were investigated in a double-blind, placebo-controlled study in 40 patients with organic brain syndrome in late life. The psychopathology was characterized by memory deficits, intellectual dysfunction, lack of drive, and disturbance of affectivity. Patients were randomly assigned to a 4-week treatment with either 2 X 400 mg oxiracetam capsules t.i.d. or identical placebo capsules in the same dosing schedule. Evaluation of the psychopathology and side effects was carried out at weeks 0, 1 and 4; laboratory tests (hematology, blood chemistry and urinalysis), a battery of psychometric tests and quantitative EEG investigations were done at weeks 0 and 4. In the oxiracetam group a slight but significant improvement in global symptomatology was observed within 1 week, with further improvement after 4 weeks. In the placebo group, an improvement was seen only in the 4th week. Evaluation of the detailed psychopathology by means of the Sandoz clinical assessment geriatric scale (SCAG) showed in the oxiracetam group significant improvements in loss of appetite and vertigo after 1 week and in short-term memory, anxiety, emotional lability, fatigue, loss of appetite and vertigo after 4 weeks. In contrast, not a single item improved significantly during placebo treatment. Although the differences in SCAG scores between the two groups failed to reach statistical significance, the overall trend towards improvement was significantly better in the oxiracetam group. The tolerability of the drug was good.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Double-blind, placebo-controlled, clinical, psychometric and neurophysiological investigations with oxiracetam in the organic brain syndrome of late life. 389 95

Anorexia is a major manifestation of zinc deficiency, but the mechanism(s) for this anorexia are not well defined. In this study we investigated the effects of three modulators of feeding response on the food consumption of zinc deficient rats. Zinc deficient rats showed partial resistance to norepinephrine, eating significantly less at the 20 micrograms dose than the zinc sufficient ad lib controls, and food ingestion could not be induced at the 10 micrograms dose. Similarly, higher doses of the GABA agonist, muscimol, were required to induce feeding in the zinc deficient animals compared to the zinc sufficient controls. The dopamine agonist, bromergocryptine, failed to induce feeding in the zinc deficient animals. These findings are compatible with the concept that zinc deficiency produces a generalized decrease in receptor responsibility, possibly secondary to alterations in membrane fluidity.
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PMID:Zinc deficiency and anorexia in rats: the effect of central administration of norepinephrine, muscimol and bromerogocryptine. 658 55

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

Brain glucose utilization was examined 24 h after single intracisternal injections of the GABA-transaminase inhibitor ethanolamine-O-sulfate (EOS) in rats. Qualitative autoradiography indicated a pronounced and homogeneous depression in [14C]2-deoxy-D-glucose ([14C]2DG) uptake throughout the brains of rats treated with 200 or 400 micrograms EOS. Quantitative scintillation counting of 14C in 9 brain areas of other rats confirmed the marked, generalized decrease in label uptake 24 h after EOS. Food intake measurements confirmed previous reports of dose-dependent anorexia after EOS. Rats treated with the 200 micrograms dose showed decreased open-field activity 24 h after injection but no other deficits in various tests of sensorimotor function or in tail-pinch-induced feeding. Rats treated with the 400 micrograms dose also showed deficits in open-field activity, plus deficits in orientation to touch stimuli, longer latencies than controls in catalepsy tests, and faster habituation of startle responses to sound. This group showed normal feeding responses to tail-pinch stimulation in the presence of solid food but not in the presence of liquid food. It was concluded that sensorimotor deficits may play some role in the anorexigenic effects of EOS but are probably not their primary cause. The discrepancy between the apparent degree of depression of brain glucose utilization and the comparatively mild behavioral deficits observed would suggest the possibility that metabolic fuels other than glucose may be mobilized following central EOS treatment.
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PMID:Central injections of the GABA-transaminase inhibitor ethanolamine-O-sulfate (EOS): effects on brain [14C]2-deoxy-D-glucose uptake and behavior in rats. 683 55

Altered brain GABA, phosphocreatine and adenosine triphosphate have been documented in paroxysmal (px) chicks in earlier studies, suggesting perturbations in energy metabolism as a causative factor in this syndrome that is characterized by spontaneous neural degeneration of several central sensory systems, grand mal seizures, and progressive anorexia. In this study, brain sections from 5-, 7-, and 10-day-old px and normal White Leghorn-cross chicks were stained by immunocytochemistry to localize and quantify GABA. Serum glucose was measured to assess adequacy of circulating energy substrate. Differences between px and normal brains were found in GABA staining intensity in nuclei and tracts associated with auditory, vestibular and oculomotor function, and in several septal areas. Staining appeared to be confined primarily to terminals, and increasingly larger numbers of stained terminals were found in older px brains. This progressive increase appears to parallel the degenerative changes that occur over time in px brain and progressive manifestation of clinical signs. Px chicks appear to have adequate circulating glucose, suggesting that alterations in brain energy substrates are not a function of inadequate supply.
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PMID:Elevated brain GABA correlates with systemic dysfunctions in paroxysmal chick. 789 2


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