Our objective is to determine the neuromodulatory role of ghrelin in the brain. To identify neurons that express the ghrelin receptor (GHS-R) we generated GHS-R-IRES-tauGFP mice by gene targeting. Neurons expressing the GHS-R exhibit green fluorescence and are clearly evident in the hypothalamus, hippocampus, cortex and midbrain. Using immunohistochemistry in combination with GFP fluorescence, we identified neurons that coexpress the dopamine receptor subtype-1 (D1R) and GHS-R. The potential physiological relevance of coexpression of these two receptors and the direct effect of ghrelin on dopamine signaling was investigated in vitro. Activation of GHS-R by ghrelin amplifies dopamine/D1R-induced cAMP accumulation. Intriguingly, amplification involves a switch in G-protein coupling of the GHS-R from G_11/q to G_i/o by a mechanism consistent with agonist dependent formation of GHS-R/D1R heterodimers. Most importantly, these results indicate that ghrelin has the potential to amplify dopamine signaling selectively in neurons that coexpress D1R and GHS-R.