Benzodiazepine-induced Hyperphagia Research Articles

α1- and α2-containing GABAA receptor modulation is not necessary for benzodiazepine-induced hyperphagia

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.

Benzodiazepine-Induced Hyperphagia: Development and Assessment of a 3D Pharmacophore By Computational Methods

Benzodiazepine receptor (BDZR) ligands are structurally diverse compounds that bind to specific binding sites on GABAA receptors and allosterically modulate the effect of GABA on chloride ion flux. The binding of BDZR ligands to this receptor system results in activity at multiple behavioral endpoints, including anxiolytic, sedative, anticonvulsant, and hyperphagic effects. In the work presented here, a computational procedure developed in our laboratory has been used to obtain a 3D pharmacophore for ligand recognition of the GABAA/BDZRS initiating the hyperphagic response. To accomplish this goal, 17 structurally diverse compounds, previously assessed in our laboratory for activity at the hyperphagic endpoint, were used. The result is a four-component 3D pharmacophore. It consists of two proton acceptor atoms, the centroid of an aromatic ring and the centroid of a hydrophobic moiety in a common geometric arrangement in all compounds with activity at this endpoint. This 3D pharmacophore was then assessed and successfully validated using three different tests. First, two BDZR ligands, which were included as negative controls in the set of seventeen compounds used for the pharmacophore development, did not fit the pharmacophore. Second, some benzodiazepine ligands known to have activity at the hyperphagia endpoint, but not included in the pharmacophore development, were used as positive controls and were found to fit the pharmacophore. Finally, using the 3D pharmacophore developed in the present work to search 3D databases, over 50 classical benzodiazepines were found. Among them, were benzodiazepine ligands known to have an effect at the hyperphagic endpoint. In addition, the novel compounds also found in this search are promising therapeutic agents that could beneficially affect feeding behavior.

Brainstem mediates diazepam enhancement of palatability and feeding: microinjections into fourth ventricle versus lateral ventricle

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.

Behavioural and neural mechanisms for benzodiazepine-induced hyperphagia: S. J. COOPER 1, S. HIGGS 1 and P. G. CLIFTON 2. 1School of Psychology, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K. and 2Laboratory of Experimental Psychology, University of Sussex, Falmer, Brighton BN1 9QG, U.K.

Behavioural and neural mechanisms for benzodiazepine-induced hyperphagia: S. J. COOPER 1, S. HIGGS 1 and P. G. CLIFTON 2. 1School of Psychology, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K. and 2Laboratory of Experimental Psychology, University of Sussex, Falmer, Brighton BN1 9QG, U.K.

A contingent, conditioned suppression of eating following chronic benzodiazepine-induced hyperphagia

While the hyperphagic effect of chloradizepoxide (CDP) has been reported by some to be enhanced with chronic drug treatment, the processes underlying this phenomenon are not well understood. In the present study, it was predicted that following chronic exposure to CDP-induced hyperphagia, animals given a placebo in place of their usual drug injection might be expected to exhibit evidence of a conditioned, drug-like response. Such a finding would then be consistent with an underlying process of behavioral sensitization. In Experiment 1a, Male Sprague-Dawley rats were randomly assigned to one of two groups receiving intraperitoneal (IP) injections of either 5 mg/kg CDP (Group CDP) or physiological saline (1 ml/kg; Group SAL) administered over 15 drug treatment days. Thirty minutes after each injection, all animals were given 30 min access to sweetened condensed milk. A significant enhancement of CDP-induced hyperphagia was observed over treatment sessions, confirming an earlier report. Unexpectedly, in the Placebo Test, the CDP animals exhibited a supression of milk consumption relative to that of the SAL group. Using the same animals, this finding was successfully replicated in Experiment 1b. In Experiment 2, it was hypothesized that if this conditioned, drug-opposite response were to reflect the involvement of some underlying compensatory, homeostatic mechanism, then it should only be observable under food-contingent conditions of chronic drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzodiazepine-induced hyperphagia: a test of the hunger-mimetic model.

The 'hunger-mimetic' model is a prominent explanatory account of benzodiazepine-induced hyperphagia. A salient feature of food deprivation (hunger) in laboratory animals is 'finicky' eating, or an enhanced reactivity to the palatability of food. If the hunger-mimetic model is correct, a similar finicky pattern of increased eating should be observed both in hungry (food-deprived) rats and in benzodiazepine-treated, hyperphagic rats. Two groups of rats were matched on measures of ad lib baseline intake of both a highly palatable food (sweetened condensed milk) and a food low in palatability (milk adulterated with 37.5 mg% quinine). Subsequently one group was placed on a moderate food deprivation schedule while the second group was maintained on ad lib food but was injected (IP) with 5 mg/kg chlordiazepoxide (CDP) 30 min prior to food presentation tests. Single-bottle tests indicated that while the food deprived animals exhibited a greater augmentation of eating when given the high-palatability food, the animals pretreated with CDP exhibited an indiscriminate elevation of eating across both foods. Similarly, on two-bottle choice tests the food-deprived rats exhibited an enhanced preference for the high-palatability food, whereas the CDP-treated animals did not change from baseline food preference. These results fail to support the hunger-mimetic model of benzodiazepine-induced hyperphagia. Alternative models based on a perseverative, disinhibitory action of benzodiazepines are discussed.

Benzodiazepine-induced hyperphagia in the nondeprived rat: Comparisons with CL 218,872, zopiclone, tracazolate and phenobarbital

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.

Clonazepam-induced hyperphagia in nondeprived rats: Tests of pharmacological specificity with R05-4864, Ro5-3663, Ro15-1788 and CGS 9896

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)

Enhancement of osmotic- and hypovolemic-induced drinking by chlordiazepoxide in rats is blocked by naltrexone

Recent reports indicate that benzodiazepine-induced hyperphagia can be antagonised by naloxone, an opiate antagonist. Benzodiazepines are also known to facilitate water ingestion in water-deprived rats, and the present study showed that in addition, benzodiazepine treatment can enhance drinking which is elicited by an osmotic thirst stimulus (2 M hypertonic saline) or by a hypovolemic thirst stimulus (20% polyethylene glycol). In both cases, low dose levels of naltrexone (also an opiate antagonist) dose-dependently suppressed the facilitation of thirst-aroused drinking by chlordiazepoxide. Taken with recent biochemical data these behavioral results indicate that the enhancement of ingestive responses by benzodiazepines may depend upon a naloxone-reversible release of endogenous opioid peptides.