Abstract
Interest in the histaminergic system as a potential target for the treatment of feeding disorders is driven by the unsatisfactory history of the pharmacotherapy of obesity. Eating behavior is regulated by a complex interplay of central neurotransmitter systems, peripheral endocrine stimuli, the circadian rhythm, and environmental cues, all factors that change the behavioral state and alter homeostatic aspects of appetite and energy expenditure. Key factors driving eating behavior are appetite and satiety that are regulated through different mechanisms. Brain histamine has long been considered a satiety signal in the nervous system. Recent observations, however, indicate that histamine does not meet the criteria for being a satiety signal, because augmented histamine release accompanies the appetitive phase of feeding behavior rather than food consumption and satiety. The appetitive phase requires a high and yet optimal arousal state, and the histaminergic system is crucial for sustaining a high degree of arousal during motivated behavior. Histamine H1 receptors in the brain are crucial for the regulation of the diurnal rhythm of food intake and the regulation of obesity; however, from a therapeutic standpoint, no brain-penetrating H1 receptor agonists have been identified that would have antiobesity effects. Despite conflicting preclinical data, insights are emerging into the potential role of histamine H3 receptors as a target of antiobesity therapeutics. The aim of this review is to outline the relevance of the histaminergic system in controlling feeding behavior and evaluate the potential therapeutic use of histaminergic ligands for the treatment of eating disorders.
Footnotes
This study was supported by the Ministero Universitá e Ricerca (I) [Grant 519MIUR068], the Universitá di Firenze (I) [Grant 519ATEN276], Cooperation in Science and Technology Action [Grant BM0806], Fondo Nacional de Desarrollo Científico y Tecnológico (Chile) [Grant 91100465], and Millenium Nucleus (Chile) [Grant P06/008-F].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.171306.
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ABBREVIATIONS:
- CNS
- central nervous system
- AAPD
- atypical antipsychotic drug
- TMN
- tuberomammillary nucleus
- α-FMH
- α-fluoromethylhistidine
- VMH
- ventromedial hypothalamus
- PVN
- paraventricular hypothalamus
- Ucp1
- uncoupling protein 1
- GLP-1
- glucagon-like peptide 1
- TRH
- thyrotropin-releasing hormone
- NTS
- nucleus of the solitary tract
- SR141716A
- N-(piperidine-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride
- PF-03654746
- (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane-1-carboxamide.
- Received June 9, 2010.
- Accepted July 20, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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