Histaminergic regulation of appetite

Food intake is essential to all animals. However, when energy consumption through food overtakes energy expenditure, obesity can result. Obesity has been identified as a worldwide health problem associated with diseases such as type 2 diabetes and hypertension. Thus, it is essential to find effective anti-obesity therapies. The aim of this thesis was to determine whether the histaminergic system could be pharmacologically manipulated to alter food intake and whether in particular the H3R is a suitable therapeutic target. Histamine is a central neurotransmitter that plays a major role in controlling energy balance by acting through specific hypothalamic sites. Injections of histamine receptor-1 (H1R) antagonists into the ventromedial hypothalamic nucleus (VMN) cause hyperphagia, whereas antagonism of presynaptic histamine receptor-3 (H3R) causes hypophagia, leading to the hypothesis that selective antagonists or inverse agonists might be potential treatments for obesity through their actions on central H3R. My aim was to assess the precise mode of action of histamine and H3R drugs to affect acute, appetitive behaviour. Using feeding and behavioural studies I demonstrated the acute anorexigenic actions of histamine (ICV) and the H3R inverse agonist, thioperamide (ICV or IP), in rats without disrupting the behavioural satiety sequence. In accordance with predictions, the H3R agonist, imetit (ICV or IP), increased feeding. The actions of both thioperamide and imetit were blocked by the drug proxyfan, which in our model is acting as a neutral H3R antagonist. Interestingly, both thioperamide and imetit caused anorexia in mice. C-Fos functional immunostaining revealed that systemic administration of thioperamide and imetit increased the activity of neurones in the key feeding nuclei of the hypothalamus, including the VMN. To further investigate the mode of action of histaminergic drugs, I carried out extracellular electrophysiological recordings from neurones of the rat VMN in vitro. Of the 197 VMN cells recorded, 62% were histamine-responsive, with 97% of these showing an increase in neuronal firing rates in response to histamine. The excitatory response to histamine was blocked in 90% of instances by pyrilamine, a selective H1R antagonist. Neurones that responded to histamine previously were treated also with thioperamide. 88% of these neurones also responded with an increase in firing. The effect of thioperamide was blocked in all cases by co-administrating pyrilamine, proving that H3R in the VMN are presynaptic autoreceptors, rather than heteroreceptors modulating the release of other transmitters. Imetit had an inhibitory effect on VMN neuronal firing in 86% of recorded cells. Proxyfan was able to block the changes in neuronal firing that both thioperamide and imetit caused. This suggests it is acting as a neutral H3R antagonist in both our in vivo and in vitro models. Thus, using a neutral H3R antagonist we have proven the effects imetit and thioperamide had on feeding and neuronal VMN firing were a direct result of activating a H3R and, therefore, these compounds are receptor-specific for the H3R. In conclusion, our results support a role for histaminergic receptors, including postsynaptic H1R and presynaptic H3R autoreceptors in the VMN, to modulate feeding.EThOS - Electronic Theses Online ServiceBBSRC : Novo NordiskGBUnited Kingdo