In mice, blocking the ghrelin receptor (GHS‑R) with a drug called D‑Lys3‑GHRP‑6 changed how they learned about rewards and how much sweet liquid they drank. Small to medium doses made the mice better at a learning test, but higher doses made them perform worse overall and made sweet water taste less appealing, so they drank less.

The orexigenic neuropeptide ghrelin is an endogeneous ligand for the growth hormone secretagogue receptor (GHS-R). This orexigen is expressed in both the periphery and in the central system, including portions of mesolimbic dopaminergic circuitry that play a role in affective behaviors. Here we examined pharmacological antagonism of GHS-R in motivational incentive learning, as reflected in Pavlovian-to-instrumental transfer (PIT). Furthermore, it is currently unclear whether the previous effects of ghrelin on food intake are mediated by pre- and/or postingestive influences on ingestive behavior. Thus, the authors also conducted detailed analyses of the temporal dynamics of sucrose licking. Mice received low (50 nmol), moderate (100 nmol), and high (200 nmol) intraperitoneal injections of the GHS-R antagonist GHRP-6 [D-Lys3] prior to subsequent transfer and sucrose consumption tests. Low and moderate doses led to an augmentation of PIT, while high dose injections led to generalized performance deficits. In addition, moderate and high doses of the antagonist resulted in reductions in sucrose intake by reducing palatability of the sucrose. These results suggest dissociable functions of GHS-R in its influence over motivational learning and ingestive behavior.