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

FG 7142 Specifically Reduces Meal Size and the Rate and Regularity of Sustained Feeding in Female Rats: Evidence that Benzodiazepine Inverse Agonists Reduce Food Palatability

“…Brain benzodiazepine receptors have been proposed to control food intake by changing the nonhomeostatic hedonic evaluation of food (for review, see Cooper, 2005), a function for which they are receiving renewed attention in the current era of obesity and disorders of binge eating. The benzodiazepine receptor is an allosteric binding site at the conjunction of a and g2 subunits (Rudolph and Möhler, 2004) of the type A gammaaminobutyric acid receptor (GABA A ).…”

“…Benzodiazepines modulate ion flux through the GABA A -gated Cl À -channel ionophore complex by altering the kinetics of channel opening and are used clinically as anxiolytic, sedativehypnotic, and anticonvulsant drugs (Chouinard, 2004;O'Brien, 2005). The effects of benzodiazepines on food intake were reported in 1960, when the agonist chlordiazepoxide was found to induce hyperphagia in both rats and dogs (Randall, 1960;Randall et al, 1960), and benzodiazepine hyperphagia was subsequently observed in other domestic and farm animals, primates and more recently, humans (Cooper, 2005). Subsequently, Cooper and coworkers, among others, showed that structurally diverse compounds with benzodiazepine site affinity bidirectionally modulate food intake according to their functional properties at the benzodiazepine receptor.…”

“…That is, food intake is promoted not only by benzodiazepines, but also by nonbenzodiazepine compounds that act as full or partial benzodiazepine receptor agonists (Cooper, 1986;Yerbury and Cooper, 1987;Chen et al, 1995), including some pyrazolopyridines, cyclopyrrolone derivatives, triazolopyridazines, pyrazoloquinolines, and b-carbolines. The orexigenic effects of such compounds are reversed by benzodiazepine antagonists, such as flumazenil (Ro 15-1788), and are not shared by stereoisomers that lack benzodiazepine receptor activity (for review, see Cooper, 2005). Conversely, compounds that are inverse agonists at the benzodiazepine receptor, including the imidazobenzodiazepines Ro 15-3505 and Ro 15-4513, some pyrazoloquinolines, and b-carbolines such as CGS 8216, DMCM, b-CMC and FG 7142, all reduce food intake (Cooper et al, , 1989Bernard et al, 1986;Patel and Ebenezer, 2002).…”

“…Conversely, compounds that are inverse agonists at the benzodiazepine receptor, including the imidazobenzodiazepines Ro 15-3505 and Ro 15-4513, some pyrazoloquinolines, and b-carbolines such as CGS 8216, DMCM, b-CMC and FG 7142, all reduce food intake (Cooper et al, , 1989Bernard et al, 1986;Patel and Ebenezer, 2002). These anorectic effects also are blocked by benzodiazepine receptor antagonists (Cooper, 2005).…”

“…Some research has questioned the behavioral specificity of feeding effects, as they might reflect changes in arousal, perseveration (Hunt et al, 1988) or anxiolytic (eg behavior disinhibiting) and anxiogenic properties of benzodiazepine receptor agonists and inverse agonists, respectively (Cooper, 2005). However, the orexigenic activities of benzodiazepine receptor agonists are pharmacologically, neuroanatomically and molecularly dissociable from their sedative/hypnotic effects, and possibly also from their anxiolytic-like effects (Cooper, 2005).…”