Palatability-dependent appetite and benzodiazepines: new directions from the pharmacology of GABA(A) 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 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.
Cooper
Steven J
SJ
Kissileff Laboratory for the Study of Human Ingestive Behaviour, School of Psychology, University of Liverpool, Liverpool L69 7ZA, UK. s.j.cooper@liverpool.ac.uk
D000818:Animals; D000855:Anorexia; D014151:Anti-Anxiety Agents; D001066:Appetite / Q000187:drug effects / Q000502:physiology*; D001569:Benzodiazepines / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D007858:Learning; D051379:Mice; D018345:Mice, Knockout; D009042:Motivation; D011963:Receptors, GABA-A / Q000502:physiology*; D009435:Synaptic Transmission; D013649:Taste / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid