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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper updates an early review on benzodiazepine-enhanced food intake, published in the first issue of Appetite, and describes the considerable advances since then in the pharmacology of benzodiazepines, their sites and mechanisms of action, and in understanding the psychological processes leading to the increase in food consumption. A great diversity of benzodiazepine receptor ligands have been developed, many of which affect food intake. Agonists can be divided into full agonists (which produce the full spectrum of benzodiazepine effects) and partial agonists (which are more selective in their effects). In addition, inverse agonists have been identified, with high affinity for benzodiazepine receptors but having negative efficacy: these drugs exhibit anorectic properties. Benzodiazepine receptors are part of GABA(A) receptor complexes, and ligands thereby modulate inhibitory neurotransmission in the brain. Molecular approaches have identified a palette of receptor subunits from which GABA(A) receptors are assembled. In all likelihood, benzodiazepine-induced hyperphagia is mediated by the alpha2/alpha3 subtype not the alpha1 subtype. Novel alpha2/alpha3 selective compounds will test this hypothesis. A probable site of action in the caudal brainstem for benzodiazepines is the parabrachial nucleus. Behavioural evidence strongly indicates that a primary action of benzodiazepines is to enhance the positive hedonic evaluation (palatability) of tastes and foodstuffs. This generates the increased food intake and instrumental responding for food rewards. Therapeutic applications may derive from the actions of benzodiazepine agonists and inverse agonists on food procurement and ingestion.
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PMID:Palatability-dependent appetite and benzodiazepines: new directions from the pharmacology of GABA(A) receptor subtypes. 1580 88

Although the role of orexins in sleep/wake cycle and feeding behavior is well established, underlying mechanisms have not been fully understood. An attempt has been made to investigate the role of GABA(A) receptors and their benzodiazepine site on the orexin-A induced response to feeding. Different groups of rats were food deprived overnight and next day injected intracerebroventricularly (icv) with vehicle (artificial CSF; 5 microl/rat) or orexin-A (20-50 nM/rat) and the animals were given free access to food. Cumulative food intake was measured during light phase of light/dark cycle at 1-, 2-, 4- and 6-h post-injection time points. Orexin-A (30-50 nM/rat, icv) stimulated food intake at all the time points (P < 0.05). Prior administration of GABA(A) receptor agonists muscimol (25 ng/rat, icv) and diazepam (0.5 mg/kg, ip) at subeffective doses significantly potentiated the hyperphagic effect of orexin-A (30 nM/rat, icv). However, the effect was negated by the GABA(A) receptor antagonist bicuculline (1 mg/kg, ip). Interestingly, benzodiazepine receptor antagonist flumazenil (5 ng/rat, icv), augmented the orexin-A (30 nM/rat, icv) induced hyperphagia; the effect may be attributed to the intrinsic activity of the agent. The results suggest that the hyperphagic effect of orexin-A, at least in part, is mediated by enhanced GABA(A) receptor activity.
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PMID:GABA(A) receptors mediate orexin-A induced stimulation of food intake. 1616 44

To investigate the role of corticolimbic input in modulating feeding-related nucleus accumbens (Acb) circuitry, researchers temporarily deactivated sites within the basolateral amygdaloid complex (BLA) or central amygdaloid region (CeA) via GABA(A) agonist (muscimol) infusions and measured feeding responses following muscimol infusions into the Acb shell. Hyperphagia elicited by intra-Acb shell muscimol was not altered by coinfusions of intra-BLA muscimol. In contrast, muscimol infusions into the CeA dose-dependently reduced feeding elicited either by intra-Acb shell GABA(A) receptor stimulation or by food deprivation and produced a syndrome of forepaw treading. Intra-CeA tetrodotoxin infusions also blocked intra-Acb shell muscimol-induced hyperphagia. Hence, feeding elicited by intra-Acb shell GABA(A) receptor stimulation requires intact neural output from the CeA but not the BLA.
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PMID:Hyperphagia induced by GABAA receptor-mediated inhibition of the nucleus accumbens shell: dependence on intact neural output from the central amygdaloid region. 1630 Apr 26

The hypothalamic regulatory system of body weight which develops in rats during critical periods of early postnatal life seems to express plastic changes depending on nutrition at that time. Adult rats previously exposed to early postnatal overnutrition by raising them in small litters become persistently predisposed to overweight, hyperphagia and hyperleptinaemia. The hypothesis was raised that feeding-related peptides could be involved through altered effects on neuronal activity of the regulatory systems of such rats. This was studied on brain slices of small-litter rats and normal-weight controls between days 60 and 120 of life. Neurons of the medial parvocellular part of the paraventricular nucleus were significantly activated by the adiposity signals leptin, insulin and amylin in controls. This is a kind of negative feedback, because activation of these neurons is known to be followed in vivo by increased energy expenditure. GABAergic mechanisms seem to affect these neuronal responses because the activating effects of insulin and amylin were reduced in the presence of a GABA(A) receptor antagonist. In overweight small-litter rats, however, the neuronal responses to the adiposity signals were significantly changed; activating effects were reduced and inhibitory effects increased. By means of blockade of GABA(A) receptors, significant alterations in the neuronal responses to leptin, insulin and amylin in small-litter rats were prevented. Responses to the peptides were reversed and now resembled those of controls. In conclusion, changes in neuronal wiring with GABAergic interneurons seem to contribute to a persistently reduced negative feedback of adiposity signals in early postnatally overfed rats.
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PMID:GABAA receptor antagonists prevent abnormalities in leptin, insulin and amylin actions on paraventricular hypothalamic neurons of overweight rats. 1655 87

Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatability. We investigated which GABA(A) receptor subtypes may be involved in mediating benzodiazepine-induced hyperphagia. The role of the alpha2 subtype was investigated by observing the effects of midazolam, on the behavioural satiety sequence in mice with targeted deletion of the alpha2 gene (alpha2 knockout). Midazolam (0.125, 0.25 and 0.5mg/kg) increased food intake and the amount of time spent feeding in alpha2 knockout mice, suggesting that BZ-induced hyperphagia does not involve alpha2-containing GABA(A) receptors. We further investigated the roles of alpha1- and alpha3-containing GABA(A) receptors in mediating BZ-induced hyperphagia. We treated alpha2(H101R) mice, in which alpha2-containing receptors are rendered benzodiazepine insensitive, with L-838417, a compound which acts as a partial agonist at alpha2-, alpha3- and alpha5-receptors but is inactive at alpha1-containing receptors. L-838417 (10 and 30 mg/kg) increased food intake and the time spent feeding in both wildtype and alpha2(H101R) mice, demonstrating that benzodiazepine-induced hyperphagia does not require alpha1- and alpha2-containing GABA(A) receptors. These observations, together with evidence against the involvement of alpha5-containing GABA(A) receptors, suggest that alpha3-containing receptors mediate BZ-induced hyperphagia in the mouse.
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PMID:Alpha1- and alpha2-containing GABAA receptor modulation is not necessary for benzodiazepine-induced hyperphagia. 1950 66