The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain?
Atypical antipsychotics such as olanzapine and clozapine are effective at treating the multiple domains of schizophrenia, with a low risk of extra-pyramidal side-effects. However a major downfall to their use is metabolic side-effects particularly weight gain/obesity, which occurs by unknown mechanisms. The present paper explores the potential candidature of histaminergic neurotransmission in the mechanisms of atypical antipsychotic-induced weight gain, with a focus on the histaminergic H1 and H3 receptors. Olanzapine and clozapine have a high affinity for the H1 receptor, and meta-analyses show a strong correlation between risk of weight gain and H1 receptor affinity. In addition, olanzapine treatment decreases H1 receptor binding and mRNA expression in the rat hypothalamus. Furthermore, a complex role is emerging for the histamine H3 receptor in the control of hunger. The H3 receptor is a pre-synaptic autoreceptor that inhibits the synthesis and release of histamine, and a heteroreceptor that inhibits other neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and acetylcholine (ACh), which are also implicated in the regulation of food intake. Thus, the H3 receptor is in a prime position to regulate food intake, both through its control of histamine and its influence on other feeding pathways. We proposed that a mechanism for atypical antipsychotic-induced weight gain may be partly through the H3 receptor, as a drug-induced decrease in H1 receptor activity may decrease histamine tone through the H3 autoreceptors, compounding the weight gain problem. In addition, atypical antipsychotics may affect food intake by influencing 5-HT, NA and ACh release via interactions with the H3 heteroreceptor.
Deng
Chao
C
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, 2522, NSW, Australia. chao@uow.edu.au
Weston-Green
Katrina
K
Huang
Xu-Feng
XF
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D004435:Eating / Q000502:physiology*; D018494:Histamine Agents / Q000494:pharmacology; D006801:Humans; D015201:Meta-Analysis as Topic; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects*
D014150:Antipsychotic Agents; D018494:Histamine Agents; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3