Brain reinforcement system function is ghrelin dependent: studies in the rat using pharmacological fMRI and intracranial self-stimulation.
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.
Behavioral Neuroscience Program, Department of Psychology, Texas A&M University, College Station, TX 77843-4235, USA. paul-wellman@tamu.edu
Paul J
PJ
Wellman
P Shane
PS
Clifford
Juan A
JA
Rodriguez
Samuel
S
Hughes
Carla
C
Di Francesco
Sergio
S
Melotto
Michela
M
Tessari
Mauro
M
Corsi
Angelo
A
Bifone
Alessandro
A
Gozzi
D000818:Animals; D019167:Appetite Stimulants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004435:Eating; D054439:Ghrelin / Q000494:pharmacology*; D013006:Growth Hormone / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000502:physiology*; D012054:Reinforcement, Psychology; D012653:Self Stimulation
D019167:Appetite Stimulants; D054439:Ghrelin; D054440:Receptors, Ghrelin; D013006:Growth Hormone