Alterations to Melanocortinergic, GABAergic and Cannabinoid Neurotransmission Associated with Olanzapine-Induced Weight Gain

Katrina Weston-Green,Xu-Feng Huang,Chao Deng,Alice Y W Chang

doi:10.1371/journal.pone.0033548

Katrina Weston-Green, Xu-Feng Huang + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0033548

Copy DOI

Abstract

Background/AimSecond generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity.Methodology/ResultsLevels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD65, enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [3H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD65 mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine.ConclusionsOlanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug.

Highlights

Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased neuropeptide Y (NPY)
This study supports a role for the CB1 receptors (CB1R) and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission
Using an established rat model of olanzapine-induced metabolic dysfunction [35,70,78,79,80], this study aimed to investigate the mechanisms underlying weight gain associated with olanzapine treatment by examining its effects on POMC, NPY and GAD65 mRNA expression, and CB1R binding density in the arcuate nucleus (Arc) and dorsal vagal complex (DVC)

Summary

Introduction

The second generation antipsychotic (SGA) olanzapine is prescribed to treat schizophrenia and a growing number of other disorders in adults and children [1,2,3,4,5,6,7,8], but can cause adverse metabolic side-effects including increased body weight [9], caloric intake [10,11] and abdominal adiposity [12,13], and reduced physical activity [14,15,16]. Weight gain during olanzapine and clozapine treatment is associated with a CB1R gene polymorphism in individuals with chronic schizophrenia [33], and chronic high-dose risperidone treatment increases cannabinoid receptor agonist, [3H]CP-55940, binding density in the Arc of male rats [34]. The effects of olanzapine on CB1R density in the Arc remain unknown

Objectives

Methods

Results

Discussion

Conclusion