title: Chronic betahistine co-treatment reverses olanzapine's effects on dopamine D₂ but not 5-HT2A/2C bindings in rat brains.
abstract: Olanzapine is widely prescribed for treating schizophrenia and other mental disorders, although it leads to severe body weight gain/obesity. Chronic co-treatment with betahistine has been found to significantly decrease olanzapine-induced weight gain; however, it is not clear whether this co-treatment affects the therapeutic effects of olanzapine. This study investigated the effects of chronic treatment of olanzapine and/or betahistine on the binding density of the serotonergic 5-HT2A (5-HT2AR) and 5-HT2C (5-HT2CR) receptors, 5-HT transporter (5-HTT), and dopaminergic D₂ receptors (D₂R) in the brain regions involved in antipsychotic efficacy, including the prefrontal cortex (PFC), cingulate cortex (Cg), nucleus accumbens (NAc), and caudate putamen (CPu). Rats were treated with olanzapine (1 mg/kg, t.i.d.) or vehicle for 3.5 weeks, and then olanzapine treatment was withdrawn for 19 days. From week 6, the two groups were divided into 4 groups (n=6) for 5 weeks' treatment: (1) olanzapine-only (1 mg/kg, t.i.d.), (2) betahistine-only (9.6 mg/kg, t.i.d.), (3) olanzapine and betahistine co-treatment (O+B), and (4) vehicle. Compared to the control, the olanzapine-only treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg, and NAc. Similar changes were observed in the rats receiving the O+B co-treatment. The olanzapine-only treatment significantly increased the D₂R binding in the Cg, NAc, and CPu, while the betahistine-only treatment reduced D₂R binding. The co-treatment of betahistine reversed the D₂R bindings in the NAc and CPu that were increased by olanzapine. Therefore, chronic O+B co-treatment has similar effects on serotonin transmission as the olanzapine-only treatment, but reverses the D₂R that is up-regulated by chronic olanzapine treatment. The co-treatment maintains the therapeutic effects of olanzapine but decreases/prevents the excess weight gain.
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522, NSW, Australia; Centre for Translational Neuroscience, School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522, NSW, Australia.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Lian
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522, NSW, Australia; Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, 2010, NSW, Australia.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522, NSW, Australia.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Pai
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522, NSW, Australia; Centre for Translational Neuroscience, School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522, NSW, Australia; Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, 2010, NSW, Australia. Electronic address: chao@uow.edu.au.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
mesh_terms: D000818:Animals; D001345:Autoradiography; D001569:Benzodiazepines / Q000494:pharmacology*; D001621:Betahistine / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017442:Histamine Agonists / Q000494:pharmacology*; D000077152:Olanzapine; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000493:pharmacokinetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D001569:Benzodiazepines; D001621:Betahistine; D017442:Histamine Agonists; D000077152:Olanzapine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium
keywords: Betahistine; Dopamine receptor; Olanzapine; Receptor binding; Serotonin receptor