Fourth ventricle injection of ghrelin decreases angiotensin II-induced fluid intake and neuronal activation in the paraventricular nucleus of the hypothalamus

Physiol Behav. 2017 Sep 1;178:35-42. doi: 10.1016/j.physbeh.2016.11.018. Epub 2016 Nov 19.


Ghrelin acts in the CNS to decrease fluid intake under a variety of dipsogenic and natriorexigenic conditions. Previous studies on this topic, however, focused on the forebrain as a site of action for this effect of ghrelin. Because the hindbrain contains neural substrates that are capable of mediating the well-established orexigenic effects of ghrelin, the current study tested the hypothesis that ghrelin applied to the hindbrain also would affect fluid intake. To this end, water and saline intakes were stimulated by central injection of angiotensin II (AngII) in rats that also received injections of ghrelin (0.5μg/μl) into either the lateral or fourth ventricle. Ghrelin injected into either ventricle reduced both water and 1.8% NaCl intake that was stimulated by AngII. The nature of the intake effect revealed some differences between the injection sites. For example, forebrain application of ghrelin reduced saline intake by a reduction in both the number of licking bursts and the size of each licking burst, but hindbrain application of ghrelin had a more selective effect on burst number. In an attempt to elucidate a brain structure in which hindbrain-administered ghrelin and forebrain-administered AngII interact to cause the ingestive response, we used Fos-immunohistochemistry in rats given the treatments used in the behavioral experiments. Although several brain areas were found to respond to either ghrelin or AngII, of the sites examined, only the paraventricular nucleus of the hypothalamus (PVN) emerged as a potential site of interaction. Specifically, AngII treatment caused expression of Fos in the PVN that was attenuated by concomitant treatment with ghrelin. These experiments provide the novel finding that the hindbrain contains elements that can respond to ghrelin and cause decreases in AngII-induced fluid intake, and that direct actions by ghrelin on forebrain structures is not necessary. Moreover, these studies suggest that the PVN is an important site of interaction between these two peptides.

Keywords: Angiotensin II; Ghrelin; Hindbrain; Paraventricular nucleus; Saline intake; Water intake.

MeSH terms

  • Angiotensin II / administration & dosage
  • Angiotensin II / metabolism*
  • Animals
  • Catheters, Indwelling
  • Central Nervous System Agents / administration & dosage
  • Drinking / drug effects
  • Drinking / physiology*
  • Drinking Behavior / drug effects
  • Drinking Behavior / physiology
  • Drinking Water / metabolism
  • Fourth Ventricle / drug effects
  • Fourth Ventricle / metabolism
  • Ghrelin / administration & dosage
  • Ghrelin / metabolism*
  • Injections, Intraventricular
  • Male
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Paraventricular Hypothalamic Nucleus / cytology
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats, Sprague-Dawley
  • Sodium Chloride / metabolism


  • Central Nervous System Agents
  • Drinking Water
  • Ghrelin
  • Proto-Oncogene Proteins c-fos
  • Angiotensin II
  • Sodium Chloride