title: Comparative effects of olanzapine and ziprasidone on hypophagia induced by enhanced histamine neurotransmission in the rat.
abstract: Atypical antipsychotic drugs (AAPDs), such as olanzapine, are associated with weight gain and hyperphagia in both humans and rodents. This side effect, however, is absent or reduced for AAPD such as ziprasidone. The increased levels of appetite seen in rodents may be related to drug interactions with brain histamine systems involved in appetite control. We demonstrate a significant interaction of olanzapine treatment with histamine neurotransmission in a rat-feeding paradigm measuring the consumption of a palatable fat emulsion. This interaction was identified using the H3 receptor antagonist thioperamide, which by blocking autoreceptor control of histaminergic neurons enhances release of hypothalamic histamine, causing hypophagia. We challenged this effect of thioperamide with olanzapine, which among its pharmacological actions is a potent H1 receptor antagonist. Olanzapine pretreatment significantly attenuated thioperamide-induced hypophagia. Pretreatment of thioperamide with ziprasidone, an AAPD with negligible H1 receptor affinity, however, failed to have this effect. Although thioperamide may also increase levels of neurotransmitters other than histamine, the potent H1 antagonist property of olanzapine is likely to result in the suppression of thioperamide-induced hypophagia. We conclude that olanzapine may be directly modulating histaminergic neurotransmission associated with the regulation of feeding behaviour.
authors.affiliation: Department of Psychology, John Maynard Smith Building, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors.forename: Nima
authors.initials: N
authors.lastname: Davoodi
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
authors.forename: Peter G
authors.initials: PG
authors.lastname: Clifton
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001066:Appetite / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D005217:Fat Emulsions, Intravenous; D006632:Histamine / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects*; D013649:Taste / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D005217:Fat Emulsions, Intravenous; D006634:Histamine H1 Antagonists; D054828:Histamine H3 Antagonists; D010879:Piperazines; D010880:Piperidines; D013844:Thiazoles; D001569:Benzodiazepines; C092292:ziprasidone; D006632:Histamine; C052075:thioperamide; D000077152:Olanzapine