Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, C01 and PC01
Histamine and its role in the regulation of appetite
R. H. Clapp1, S. M. Luckman1
1. Faculty of Life Sciences, University of Manchester, Manchester, Lancashire, United Kingdom.
Food intake is essential to all animals. By ingesting food an animal obtains energy to survive. However, food intake must be balanced with energy expenditure otherwise overeating results in obesity. Due to the imbalance between energy intake and output obesity has become is a major worldwide problem. We aim to look at the effects of the central transmitter, histamine, on appetite regulation by measuring feeding behaviour, the induction of the functional marker c-Fos and the electrical activity of histamine responding neurones within the ventromedial hypothalamus (VMN). Pharmacological studies suggest two histamine receptors regulate food intake, H1R and H3R. Activation of central H1R and H3R leads to a decrease and an increase in food intake, respectively. Our preliminary studies confirmed that 200 nmol histamine given centrally via an intracerebral guide cannula (implanted 1 week prior under 2% isofluorane in O2 at 1 l/min anaesthesia) is a powerful anorexigen. Examining the effects of H3R active drugs in rats revealed imetit, a H3R agonist, caused hypophagia whilst the H3R inverse agonist thioperamide resulted in hyperphagia. Both thioperamide and imetit can be blocked by proxyfan which, therefore, appears to be acting as a neutral H3R antagonist. Interestingly murine studies showed both the H3R agonist and H3R antagonist caused a decrease in night time feeding which contradicts previously published research. Using c-Fos immunohistochemistry we found the effects of histamine and H3R based drugs most likely involve the major hypothalamic nuclei involved in homeostatic regulation of body weight; namely the VMN, paraventricular, dorsomedial and arcuate nuclei. Furthermore, extracellular electrophysiological recordings in vitro demonstrate that these effects are likely to be direct on the hypothalamus. For example, histamine activates the majority of VMN neurones (60%). By applying histamine with the H1R antagonist pyrilamine, we have managed to diminish the excitatory actions of histamine responding neurones within the VMN. We also have evidence for local presynaptic H3R involvement. Our results show that by applying thioperamide, a H3R antagonist, we can mimic the actions of histamine causing an increase in the firing rate of neurones within the VMN. Additionally, this increase in neuronal firing caused by thioperamide application can be blocked by applying pyrilamine. These results demonstrate VMN H3R are presynaptic autoreceptors on histaminergic afferents, rather than heteroreceptors modulating the release of other transmitters. Finally we have found that the neutral H3R antagonist proxyfan can attenuate the neuronal response of thioperamide suggesting a direct H3R response. Thus our data supports a role for histaminergic receptors, including postsynaptic H1R and presynaptic H3R autoreceptors in the VMN, to modulate feeding.
Where applicable, experiments conform with Society ethical requirements