Our objective is to provide therapeutic intervention that will maintain high quality of life during aging. We developed small molecules that restore the physiological profile of episodic growth hormone (GH) release in the elderly to that of young adults and then cloned the orphan G-protein coupled receptor (GPCR) mediator involved, naming it the growth hormone secretagogue receptor (GHS-R). Subsequently, Kojima identified the endogenous agonist, ghrelin; hence, the small molecule GHS-R agonists are referred to as ghrelin mimetics. In the frail elderly, chronic administration of a ghrelin mimetic, MK677, to rejuvenate the GH axis, was accompanied by increased bone density, lean mass and strength. Therefore, we concluded that MK677 rescued an age-dependent deficit in endogenous ghrelin signaling. Aside from the GH axis, this deficit could have more profound consequences during aging because the GHS-R (ghrelin receptor) localizes to neurons regulating mood, memory and learning. The dopamine receptor subtype-1 (D1R) is coexpressed in these same neurons, implicating ghrelin as a modulator of dopamine signaling. Indeed, in cells coexpressing GHS-R and D1R, ghrelin amplifies dopamine-induced accumulation of cAMP. To investigate the broad significance of neuromodulation by ghrelin, GHS-R modulation of D1R, GH-releasing hormone (GHRH) receptor, and somatostatin receptors (sst5 and sst2) signaling will be compared. These GPCR partners are endogenously coexpressed with the GHS-R in vivo and regulate cAMP signaling. Mechanistic studies will investigate: adenylyl cyclase (AC) activity; identifying AC-isozymes involved; modification of Ga subunits; [unreadable]y-subunit scavenging; GHS-R/GPCR heterodimerization. Specific Aims: define the molecular mechanism of amplification of dopamine D1R-induced cAMP accumulation caused by co-activation of the ghrelin receptor (GHS-R), and test the hypothesis in wildtype, ghrelin-/- and ghrelin receptor knockout mice (Ghsr-/-) that ghrelin-mediated amplification occurs in vivo to enhance signaling in D1R and GHS-R expressing neurons resulting in behavioral changes; determine the molecular mechanism of how ghrelin activation of GHS-R amplifies GHRH receptor-mediated cAMP accumulation and contrasts with amplification of D1R-induced cAMP accumulation; determine the molecular mechanism of how ghrelin activation of GHS-R attenuates the inhibitory effects sst5-signaling on cAMP accumulation, compare with sst2, and determine whether sst5 and sst2 are coexpressed with the GHS-R in brain. Because of ghrelin's broad modulatory role on signaling in the brain, rescuing age-related deficits in endogenous ghrelin signaling has broad human health implications. Augmentation of dopamine signaling by ghrelin in the elderly is directly relevant to aging and Parkinson's disease, because learning and memory are improved by increasing cAMP accumulation in neurons. We hypothesize that clinical use of ghrelin mimetics will translate to improved cognitive function in the elderly. [unreadable] [unreadable] [unreadable]