5HT(1A) RECEPTOR ANTAGONISTS ENHANCE THE FUNCTIONAL-ACTIVITY OF FLUOXETINE IN A MOUSE MODEL OF FEEDING

Fluoxetine has been reported to suppress food intake in animal models of feeding. Fluoxetine increases extracellular serotonin in the brain. 5HT(1A) autoreceptors regulate synaptic levels of serotonin. A combin ation of a 5HT(1A) receptor antagonist and fluoxetine has been previou sly reported to enhance extracellular levels of serotonin over what is obtained with fluoxetine alone. Thus, a combination of fluoxetine and a 5HT(1A) antagonist could enhance the ability of fluoxetine to suppr ess appetite. Fluoxetine was tested in a model of feeding, in which CD -1 mice were trained to drink sweetened condensed milk. Fluoxetine was found to attenuate milk drinking, in a dose-dependent manner, at dose s greater than 10 mg/kg, i.p. A 10 mg/kg dose of fluoxetine, which was ineffective by itself, was then combined either with 5-hydroxytryptop han (5HTP), a serotonin precursor, or with S(-) pindolol, a 5HT(1A)/be ta adrenergic receptor antagonist or with LY206130, a more selective 5 HT(1A) receptor antagonist. These treatment paradigms resulted in sign ificant attenuation of the consumption of sweetened condensed milk. Si nce fluoxetine has been shown to be useful in the treatment of eating disorders and to promote weight loss in obese humans, although at dose s greater than those required for the treatment of depression, a combi nation of fluoxetine with a 5HT(1A) receptor antagonist could be of cl inical utility in the treatment of eating disorders and obesity. (C) 1 998 Elsevier Science B.V.