title: 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.
abstract: Benzodiazepine receptor inverse agonists reduce food intake in males, but their actions in females, in whom stress-related eating disorders are more common, as well as their behavioral mode of action remain unclear. The consummatory effects of benzodiazepine receptor ligands have alternately been hypothesized to reflect changes in the hedonic evaluation of food or secondary effects of anxiety-related or cognitive properties. To test the anorectic mode of action of benzodiazepine inverse agonists, the effects of FG 7142 on feeding microstructure were studied in nondeprived female Wistar rats (n=32). Microstructure analysis used a novel meal definition that recognizes prandial drinking. On pharmacologically synchronized diestrus I, rats were pretreated (-30 min dark onset) with the benzodiazepine partial inverse agonist FG 7142 (i.p. 0, 3.75, 7.5, 15 mg/kg) in a between-subjects design. FG 7142 delayed the onset of (16-541%), decreased the amount eaten (36-52%) and drunk (63-87%), and reduced the time spent drinking (59-87%) within the first nocturnal meal. Dose-dependent incremental anorexia continued 6 h into the dark cycle, whereas FG 7142 did not suppress the quantity, duration or rate of drinking past the first meal. Treated rats ate smaller meals (17-42%) of normal duration. This reflected that FG 7142 slowed feeding within meals (9-38%) by decreasing the regularity and maintenance of feeding from pellet-to-pellet. FG 7142 did not influence postprandial satiety; meal frequency and inter-meal intervals were unaffected. FG 7142 anorexia was blocked by the benzodiazepine receptor antagonist flumazenil in a 2:1 molar ratio (n=17 rats). The very early, nonspecific (+10 min), but not subsequent (2.5, 4.5 h) feeding-specific phase, of FG 7142 anorexia was mirrored by anxiogenic-like behavior in FG 7142-treated (7.5 mg/kg) female rats (n=48) in the elevated plus-maze. Thus, benzodiazepine receptor inverse agonists preferentially lessen the maintenance of feeding in female rats, effects opposite to those of palatable food.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA. cottone@scripps.edu
authors.forename: Pietro
authors.initials: P
authors.lastname: Cottone
authors.forename: Valentina
authors.initials: V
authors.lastname: Sabino
authors.forename: Luca
authors.initials: L
authors.lastname: Steardo
authors.forename: Eric P
authors.initials: EP
authors.lastname: Zorrilla
mesh_terms: D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D001008:Anxiety Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D001066:Appetite / Q000187:drug effects* / Q000502:physiology; D001067:Appetite Depressants / Q000494:pharmacology; D001069:Appetite Regulation / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology
chemical_list: D001067:Appetite Depressants; D002243:Carbolines; D018756:GABA Antagonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D005442:Flumazenil; C035874:FG 7142