title: Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density.
abstract: Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either olanzapine (1mg/kg), betahistine (2.7 mg/kg), olanzapine plus betahistine (O+B), or vehicle (control) for 2 weeks. Quantitative autoradiography was used to detect the density of [(3)H]ketanserin, [(3)H]paroxetine and [(3)H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, olanzapine significantly decreased [(3)H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [(3)H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both olanzapine only and O+B co-treatment did not affect [(3)H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce olanzapine-induced weight gain side-effects without affecting olanzapine's actions on 5-HT2AR transmissions.
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522 NSW, Australia; Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, 2522 NSW, Australia.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Lian
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.forename: Nagesh
authors.initials: N
authors.lastname: Pai
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography; D001569:Benzodiazepines / Q000494:pharmacology*; D001621:Betahistine / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D001931:Brain Mapping; D004338:Drug Combinations; D005260:Female; D000077152:Olanzapine; D011485:Protein Binding / Q000187:drug effects; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D004338:Drug Combinations; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D050486:Serotonin Plasma Membrane Transport Proteins; D001569:Benzodiazepines; D000077152:Olanzapine; D001621:Betahistine
keywords: 5-HT; 5-HT transporter; 5-HT(2A) receptor; 5-HT(2A)R; 5-HTT; ANOVA; Betahistine; CPu; Cg; D(2)R; Dopamine D(2) receptor; EPS; FGAs; H(1)R; H(3)R; M(1) receptor; M(1)R; NAcC; NAcS; Olanzapine; PFC; RT; Receptor binding; SGAs; SN; VTA; analysis of variance; caudate putamen; cingulate cortex; dopamine D(2) receptor; extrapyramidal symptoms; first generation antipsychotic drugs; histamine H(1) receptor; histamine H(3) receptor; nucleus accumbens, core; nucleus accumbens, shell; prefrontal cortex; room temperature; second generation antipsychotic drugs; serotonin; serotonin (2A) receptor; serotonin transporter; substantia nigra; ventral tegmental area; α(1-2)R; α(1–2) receptor