Midbrain raphe 5-HT_1A receptor activation alters the effects of ghrelin on appetite and performance in the elevated plus maze

Abstract

Prior research suggests that midbrain serotonergic signaling and hypothalamic ghrelinergic signaling both play critical roles in appetitive and emotional behaviors. In the present study, we investigated the effects of median raphe nucleus (MRN) somatodentritic 5-HT1A receptor activation on the feeding-stimulant and anxiogenic action of paraventricular nucleus (PVN) ghrelin. In an initial experiment, adult male Sprague-Dawley rats were injected with either ghrelin (200-800 pmol) into the PVN or 8-OH-DPAT (2.5-10 nmol), a 5-HT1A receptor agonist, into the MRN. Performance on the elevated plus maze (EPM) was then assessed. In separate rats, MRN 8-OH-DPAT (2.5-5 nmol) was administered 5 min prior to PVN injection of ghrelin (400 pmol) followed by EPM testing. The orexigenic effects of MRN 8-OH-DPAT (0.1-1.6 nmol) paired with PVN ghrelin (50 pmol) were also examined. When administered alone into the PVN, ghrelin significantly decreased the number of entries and time spent in the open arms of the EPM. This anxiogenic effect was blocked if rats were allowed to eat immediately after ghrelin administration and then tested in the plus maze. MRN injections of 8-OH-DPAT were anxiolytic, and when rats were pretreated with 8-OH-DPAT prior to ghrelin, the anxiogenic action of the peptide was attenuated. In contrast, MRN administration of 8-OH-DPAT potentiated the eating-stimulant effect of PVN ghrelin. Overall, our findings demonstrate that ghrelinergic and serotonergic circuits interact in the neural control of eating and anxiety-like behaviors, with 5-HT1A receptor mechanisms potentiating the orexigenic action of ghrelin while inhibiting ghrelin-induced anxiogenesis as measured via the EPM.

Electrophysiological Effects of Ghrelin in the Hypothalamic Paraventricular Nucleus Neurons

“…Indeed, intra-PVN administration of ghrelin showed similar sympathetic-dependent inhibition of the brown-adipose tissue (Mano-Otagiri et al, 2009), and increases FOS in the nucleus of the solitary tract (Olszewski et al, 2003). Additionally, non-secretory PVN neurons may participate in ghrelin effects on other physiological functions such as anxiety-like behavior (Currie et al, 2012; Wauson et al, 2015) and feeding (Wren et al, 2001; Melis et al, 2002; Olszewski et al, 2003; Shrestha et al, 2004) which are increased by intra-PVN administration of ghrelin.…”

The actions of ghrelin in the paraventricular nucleus: energy balance and neuroendocrine implications

“…The increase in food intake in response to intra‐PVN administration of ghrelin is blunted by subcutaneous administration of l ‐NAME, a nitric oxide (NO) synthase inhibitor, indicating that the endogenous production of NO is necessary for the action of ghrelin . Similarly, serotoninergic neurons from the mesencephalic raphe nuclei project to the PVN and serotonin decreases ghrelin‐induced food intake suggesting that these neurons increase the activity of anorexigenic neurons in the PVN. Acute administration of a 5‐HT1a receptor agonist into the median raphe nucleus increases the orexigenic effect of intra‐PVN injected ghrelin, strongly indicating that serotoninergic neurons block the effects of ghrelin in PVN neurons.…”

“…Similarly, serotoninergic neurons from the mesencephalic raphe nuclei project to the PVN and serotonin decreases ghrelin‐induced food intake suggesting that these neurons increase the activity of anorexigenic neurons in the PVN. Acute administration of a 5‐HT1a receptor agonist into the median raphe nucleus increases the orexigenic effect of intra‐PVN injected ghrelin, strongly indicating that serotoninergic neurons block the effects of ghrelin in PVN neurons. Food intake in response to intra‐PVN administration of ghrelin is also reversed by the previous microinjection of urocortin‐I or NPY Y5 receptor antagonist .…”

“…The effects of ghrelin on respiratory exchange ratio are also reversed by pretreatment with urocortin I, serotonin, or 5‐HT2A/2C receptor agonists, which suggests that these neurotransmitters modulate this response. Indeed, acute administration of a 5‐HT1a receptor agonist into the median raphe nucleus increases the orexigenic effect of PVN ghrelin, strongly indicating that serotoninergic neurons block the effects of ghrelin on PVN neurons. PVN ghrelin administration increases gastrointestinal motility, an effect that is blocked by coadministration of a GHSR antagonist.…”

Regulation of motivation for food by neuromedin U in the paraventricular nucleus and the dorsal raphe nucleus

“…However, its regulation of reinforcement behavior via serotonin signaling has been reported (49) and recent research demonstrates that food reinforcement activates serotonin neurons within the DRN (50). Additionally, PVN ghrelin signaling regulates appetite through DRN serotonin signaling (51). As ICV NMU has been demonstrated to alter serotonin expression in the brain, and the behavioral effects of NMU are regulated by serotonin receptor function (52), NMU may regulate food reinforcement via serotonin signaling downstream of the DRN.…”