Brain reinforcement system function is ghrelin dependent: studies in the rat using pharmacological fMRI and intracranial self-stimulation.
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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 A, whereas GHR-R null rats required 300 A for ICSS shaping. No differences in rate-frequency curves were noted for WT rats at 75 A and GHR-R null rats at 300 A. When current intensity was lowered to 100 A, 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.
Wellman, P. J., Clifford, P. S., Rodriguez, J. A., Hughes, S., Di Francesco, C., Melotto, S., ... Gozzi, A.
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Wellman, Paul J||Clifford, P Shane||Rodriguez, Juan A||Hughes, Samuel||Di Francesco, Carla||Melotto, Sergio||Tessari, Michela||Corsi, Mauro||Bifone, Angelo||Gozzi, Alessandro