The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the
growth hormone secretagogue receptor 1a (GHS-R1A) are pivotal regulators of hypothalamic
feeding centers and reward processing neuronal circuits of the brain. These systems
operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter
messages and metabolic signals. Functional magnetic resonance imaging was employed
in the current study to map BOLD responses to ghrelin in different brain regions with
special reference on homeostatic and hedonic regulatory centers of energy balance.
Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced
rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied.
Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after
administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response
in all studied regions of interest (ROI) within the limbic system. This effect was
antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin
effects in the presence or absence of JMV2959 in individual ROIs revealed significant
changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also
within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular
nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost
identical to those observed in males. Ovariectomy and chronic estradiol replacement
had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by
rimonabant significantly attenuated the response of the nucleus accumbens and septum.
In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling
energy balance in both sexes. The endocannabinoid signaling system contributes to
the manifestation of ghrelin's BOLD effect in a region specific manner. In females,
the estradiol milieu does not influence the BOLD response to ghrelin.
