Palatability-dependent appetite and benzodiazepines: new directions from the pharmacology of GABAA receptor subtypes

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 GABAA receptor complexes, and ligands thereby modulate inhibitory neurotransmission in the brain. Molecular approaches have identified a palette of receptor subunits from which GABAA receptors are assembled. In all likelihood, benzodiazepine-induced hyperphagia is mediated by the α2/α3 subtype not the α1 subtype. Novel α2/α3 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.