For these experiments, we selected the DRD2 agonist cabergoline. Cabergoline

is widely used clinically for treatment of Parkinson disease and hyperprolactinemia and has greater selectivity for DRD2 compared to other dopamine and serotonin receptor subtypes (Kvernmo et al., 2006). Besides other pathways, DRD2 regulates feeding behavior (Fetissov et al., 2002 and Palmiter, 2007), and humans treated with cabergoline experience weight loss (Korner et al., 2003). Because the hypothalamus is a key regulatory center for food intake, we hypothesized that cabergoline acts on these neurons to induce anorexia. Pharmacological doses of ghrelin increase food intake, therefore, it is possible that cabergoline inhibits food intake by lowering endogenous ghrelin concentrations, or by interfering with ghrelin signaling. Alternatively, cabergoline suppression of feeding may require selleck the allosteric effect of GHSR1a on DRD2 signaling. To

test these possibilities, we compared food intake in ghsr+/+ mice and ghsr−/− mice treated with cabergoline. If cabergoline interfered with endogenous ghrelin signaling, food intake should be inhibited in both genotypes and perhaps exaggerated in ghsr−/− mice; however, ghsr−/− mice were completely refractory to cabergoline-induced anorexia, illustrating dependence on GHSR1a. To test whether the allosteric interaction between DRD2 and GHSR1a could be targeted pharmacologically, we treated mice with the highly selective neutral GHSR1a antagonist JMV2959 prior to cabergoline treatment. As predicted by our hypothesis, Carfilzomib JMV2959 blocked Phosphoprotein phosphatase cabergoline-induced anorexia. The demonstration that JMV2959 treatment of WT mice recapitulates the phenotype observed in ghsr−/− mice indicates that resistance

of ghsr−/− mice to cabergoline is further evidence of an allosteric function for GHSR1a on DRD2-mediated inhibition of food intake. This result also argues against possible developmental changes caused by ghsr ablation as an explanation of the resistance of ghsr−/− mice to cabergoline. Although counter to evidence that ghrelin stimulates rather than inhibits feeding behavior, the unlikely possibility remained that blocking endogenous ghrelin signaling with either a GHSR1a antagonist or ablation of ghsr might overcome the inhibitory effect of cabergoline on food intake. If this were true, then ghrelin−/− mice, like ghsr−/− should be resistant to the anorexic effect of cabergoline. When food intake was compared in vehicle-treated and cabergoline-treated ghrelin+/+ and ghrelin−/− mice, suppression of food intake by cabergoline was identical in both genotypes. These results provide additional evidence that cabergoline-induced anorexia is dependent upon allosteric interactions between GHSR1a and DRD2.