Central apelin administration and restraint stress induce hypothalamic cholecystokinin release via the APJ receptor

Exposure to an acute stressor induces up‐regulation of apelin and cholecystokinin (CCK) in the hypothalamic paraventricular nucleus (PVN), which is the key brain centre integrating the stress‐induced alterations in neuroendocrine, autonomic and behavioural functions. We tested the hypothesis that th...

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Published in:Journal of neuroendocrinology 2018-09, Vol.30 (9), p.e12635-n/a
Main Authors: Bülbül, Mehmet, Sinen, Osman, Abueid, Leyla, Akkoyunlu, Gökhan, Özsoy, Özlem
Format: Article
Language:English
Subjects:
apelin
APJ receptor
Autonomic nervous system
Cholecystokinin
Enzyme immunoassay
Heart rate
heart rate variability
Hypothalamus
Immunofluorescence
Immunoreactivity
Microdialysis
Paraventricular nucleus
Potassium chloride
Rodents
stress
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Summary:Exposure to an acute stressor induces up‐regulation of apelin and cholecystokinin (CCK) in the hypothalamic paraventricular nucleus (PVN), which is the key brain centre integrating the stress‐induced alterations in neuroendocrine, autonomic and behavioural functions. We tested the hypothesis that the release of CCK from the PVN is increased by centrally administered or stress‐induced up‐regulated endogenous apelin via the APJ receptor. Additionally, the effect of hypothalamic CCK on autonomic outflow was investigated under basal and stressed conditions. In vivo brain microdialysis was performed in rats that received (i) intra‐PVN administration of apelin‐13 or (ii) acute restraint stress (ARS). For chemical stimulation of the neurones in the PVN, a high concentration of KCl was applied by reverse microdialysis. CCK‐8 levels in microdialysates were quantified by an enzyme immunoassay. The immunoreactivity of the APJ receptor and CCK was detected by immunofluorescence in hypothalamic sections. Heart rate variability was assessed in rats that received PVN stimulation or ARS following pre‐administration of vehicle or CCK1 receptor antagonist lorglumide. Both intra‐PVN exogenous apelin‐13 and ARS increased the CCK‐8 levels in dialysates significantly. The ARS‐induced elevations in CCK levels were reversed by intra‐PVN pre‐administration of the APJ receptor antagonist F13A. Within the PVN, robust APJ receptor expression was detected on the CCK‐producing mediocellular cells, in addition to the parvocellular neurones in the periventricular region. Dual immunoreactivity of APJ/CCK was observed in magnocellular cells to a lesser degree. Both exogenous apelin and ARS increased the CCK immunoreactivity markedly within the PVN, which was diminished significantly by F13A. Sympathetic tonus was increased markedly both by PVN stimulation and ARS, which was attenuated by lorglumide. These results revealed the interaction between apelin and CCK in the brain, suggesting that hypothalamic CCK may contribute to the apelin‐induced alterations in autonomic outflow under stressed conditions.
ISSN:0953-8194
1365-2826
DOI:10.1111/jne.12635