Brain reinforcement system function is ghrelin dependent: studies in the rat using pharmacological fMRI and intracranial self-stimulation

ABSTRACT Ghrelin (GHR) is an orexigenic gut peptide that interacts with brain ghrelin receptors (GHR‐Rs) to promote food intake. Recent research suggests that GHR acts as a modulator of motivated behavior, suggesting a direct influence of GHR on brain reinforcement circuits. In the present studies, we investigated the role of GHR and GHR‐Rs in brain reinforcement function. Pharmacological magnetic resonance imaging was used to spatially resolve the functional activation produced by systemic administration of an orexigenic GHR dose. The imaging data revealed a focal activation of a network of subcortical structures that comprise brain reinforcement circuits—ventral tegmental area, lateral hypothalamus and nucleus accumbens. We next analyzed whether brain reinforcement circuits require functional GHR‐Rs. To this purpose, wild‐type (WT) or mutant rats sustaining N‐ethyl‐N‐nitrosourea‐induced knockout of GHR‐Rs (GHR‐R null rats) were implanted with stimulating electrodes aimed at the lateral hypothalamus, shaped to respond for intracranial self‐stimulation (ICSS) and then tested using a rate‐frequency procedure to examine ICSS response patterns. WT rats were readily shaped using stimulation intensities of 75 µA, whereas GHR‐R null rats required 300 µA for ICSS shaping. No differences in rate‐frequency curves were noted for WT rats at 75 µA and GHR‐R null rats at 300 µA. When current intensity was lowered to 100 µA, GHR‐R null rats did not respond for ICSS. Taken collectively, these data suggest that systemic GHR can activate mesolimbic dopaminergic areas, and highlight a facilitative role of GHR‐Rs on the activity of brain reinforcement systems.