Histaminergic regulation of appetite through H1R and H3R in the ventromedial hypothalamic nucleus

Rachel Clapp, Stella Macharia, Simon Luckman. 1University of Manchester, Manchester, United Kingdom, 2Novo Nordisk, Copenhagen, Denmark.

Histamine 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. We confirmed the acute anorexigenic actions of histamine (i.c.v.) and the H3R inverse agonist, thioperamide (i.c.v. or i.p.), in rats, and that these treatments do not disrupt the behavioural satiety sequence. Conversely, the H3R agonist, imetit (i.c.v. or i.p.) had opposing effects causing increased feeding. Both thioperamide and imetit were blocked by proxyfan which, therefore, appears to be acting as a neutral H3R antagonist. C-fos functional immunostaining revealed systemic thioperamide increased neuronal activity in the hypothalamus, including the VMN. To further investigate mode of action of histaminergic drugs, we used extracellular electrophysiology on VMN neurones in vitro. Histamine increased firing rate in 69% of recorded neurones and decreased firing in only 5%. The other neurones displayed no response. The selective H1R antagonist, pyrilamine, blocked the excitatory response to histamine in 77% of instances. 100% of the histamine-responsive neurones tested, also increased firing when thioperamide was administered alone. The excitatory response to thioperamide was blocked by co-administration of pyrilamine in 93% of the cells tested. These results demonstrate VMN H3R are presynaptic autoreceptors on histaminergic afferents, rather than heteroreceptors modulating the release of other transmitters. Our data supports a role for histaminergic receptors, including postsynaptic H1R and presynaptic H3R autoreceptors in the VMN, to modulate feeding.