NAP2022-I-10/2022(Nemzeti Agykutatási Program) Funder: MTA
Discovery Grant(06248)
National Brain Research Program of the Hungarian Academy of Sciences(NAP 3.0)
Ghrelin enhances feeding by activating the growth hormone secretagogue receptor (GHSR).
In the brain, GHSRs are expressed in regions responsible for regulating food motivation
including the ventral tegmental area (VTA). Endogenous cannabinoids also promote food
seeking behaviors through the cannabinoid receptor 1 type (CB-1Rs) in brain regions
including the VTA. It is not known, however, if ghrelin and endocannabinoids interact
in the VTA to produce these effects. We therefore examined if GHSR and CB-1R interact
within the VTA to enhance food motivation. Results show that GHSR and CB-1R mRNA are
expressed in the VTA cells in male and female rats and mice, with the GHSR being expressed
in dopamine cells, and the CB-1R being expressed primarily in non-dopaminergic cells
with no obvious sex differences. Ghrelin directly activated and increased excitatory
tone onto dopamine cells of male and female mice. Male rats lacking fully functional
GHSR signalling showed disrupted gene expression of transcripts important for regulating
the synthesis, release, and degradation of endocannabinoids and lowered the levels
of 2-arachidonoylglycerol (2-AG) within the VTA. Moreover, pharmacological antagonism
of VTA CB-1Rs attenuates the orexigenic and appetitive effects of intra-VTA ghrelin
in rats and blocks the ability of ghrelin to promote excitatory drive to VTA dopamine
neurons. Finally, blocking the breakdown of cannabinoids in the VTA enhances the effects
of ghrelin on food motivation. Together, our data show that ghrelin stimulates VTA
dopamine cells and ultimately food motivation in part through a mechanism that involves
endocannabinoid signalling at the CB-1R.
