Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats

Weston–Green, Katrina; Huang, Xu‐Feng; Deng, Chao

doi:10.1016/j.bbr.2010.10.039

Cited by 96 publications

(100 citation statements)

References 96 publications

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“…Clinical data has indicated ghrelin production and signalling is upregulated, at least in a subpopulation of patients under SGA treatments (Esen-Danaci et al, 2008;Murashita et al, 2007a;Murashita et al, 2005;Palik et al, 2005;Perez-Iglesias et al, 2008), which was supported by the majority of acute and chronic animal studies (Murashita et al, 2007b;van der Zwaal et al, 2012;Weston-Green et al, 2011). Although ghrelin signalling is only indirectly related to SGAs, and therefore other mechanisms (for example, antagonism of H1, H3, 5-HT2a, M3 receptors) cannot be excluded, the majority of data as discussed above indicate that the altered ghrelin signalling under SGA treatments can at least partly explain the weight gain sideeffects induced by SGAs.…”

Section: Conclusion and Clinical Implicationsmentioning

confidence: 85%

“…Ghrelin could increase food intake and lead to body weight gain in humans (Adachi et al, 2010;Druce et al, 2005), which coincides with clinical observations that patients on antipsychotics often experience increased appetite and food intake. In addition, clinical (Basoglu et al, 2010;Chen et al, 2011;Esen-Danaci et al, 2008;Hosojima et al, 2006;Kim et al, 2008;Murashita et al, 2007a;Murashita et al, 2005;Palik et al, 2005;Perez-Iglesias et al, 2008;Roerig et al, 2008;Tanaka et al, 2008;Togo et al, 2004;Vidarsdottir et al, 2010) and animal studies (Albaugh et al, 2006;Davey et al, 2012;Weston-Green et al, 2011) suggest that SGA treatments modulate circulating ghrelin levels. Moreover, rats treated with olanzapine, an SGA with significant weight gain liabilities, have elevated hypothalamic ghrelin receptor (also called growth hormone secretagogue receptor 1a; GHS-R1a) expression (Davey et al, 2012;Zhang et al, 2012), indicating that ghrelin signalling may play a role in antipsychotic-induced obesity.…”

Section: Introductionmentioning

confidence: 99%

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The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

Zhang¹,

Deng²,

Huang³

2013

Psychoneuroendocrinology

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Based on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGA-induced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium. Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome. ABSTRACTBased on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGAinduced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium.Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/ agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome.

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Section: Conclusion and Clinical Implicationsmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

Zhang¹,

Deng²,

Huang³

2013

Psychoneuroendocrinology

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“…The olanzapine dosage used in this study (1 mg/kg, t.i.d. ) has been shown to be pharmacologically effective in affecting central receptor systems relative to its pharmacological profile (Han et al, 2008b, Han et al, 2009a, Han et al, 2009b, Weston-Green et al, 2011, as well as behaviourally effective in affecting locomotor activity and food intake, and producing the obesity phenotype in rats (Han et al, 2008a, WestonGreen et al, 2011. The dosage of betahistine (2.67 mg/kg, t.i.d.)…”

Section: Discussionmentioning

confidence: 99%

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

Lian

Huang

Pai

et al. 2013

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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. 2013, 'Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density ', vol. 47, Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density AbstractOlanzapine 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

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“…Female rats were chosen in this study, both because risperidone-induced weight gain has been reported in a previous study using female juvenile rats [49] and also because, while SGA-induced weight gain has been consistently established in females using various SGAs including risperidone and olanzapine [27,32,38,40,[50][51][52][53], it could not be consistently modelled in male rodents. While risperidone-induced weight gain has been well modelled in female rodents [49,[52][53][54], it has been established in male rats in some studies [34] but not in others [35,54,55].…”

Section: Choice Of Female Ratsmentioning

confidence: 99%

“…Therefore, in this study, we investigated the effects of risperidone on body weight and food intake in female juvenile rats and further investigated its effects on expression of hypothalamic H 1 R, NPY, POMC, AgRP and CART mRNA expression, and their relationships with changes in body weight gain and food intake. Since our recent studies in adult rat models have demonstrated that olanzapine-induced weight gain is associated with a significant decrease in locomotor activity [38][39][40], and decreased activity was also observed after acute administration of antipsychotics during early development [41], the locomotor activity of female juvenile rats was also examined in this study.…”

Section: Introductionmentioning

confidence: 99%

Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways

Lian

Santis

et al. 2015

Pharmacological Research

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. (2015). Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: the role of histaminergic and NPY pathways. Pharmacological Research,[95][96] Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: the role of histaminergic and NPY pathways AbstractSecond generation antipsychotic drugs (SGAs) such as risperidone are increasingly prescribed (mostly for offlabel use) to children and adolescents for treating various mental disorders. SGAs cause serious weight gain/ obesity and other metabolic side-effects. This study aimed to establish an animal model of risperidoneinduced weight gain in female juvenile rats, and to investigate the effects of risperidone on the expression of hypothalamic histaminergic H1 receptors (H1R) and neuropeptides, and their association with weight gain. Female Sprague Dawley rats were treated orally with risperidone (0.3 mg/kg, 3 times/day) or vehicle (control) starting from postnatal day (PD) 23 (±1 day) for 3 weeks (a period corresponding to the childhoodadolescent period in humans). In the female juvenile rats, risperidone treatment increased food intake and body weight gain, which started to appear after 12 days' treatment. Risperidone also significantly decreased the locomotor activity of the female rats. Consistently, risperidone significantly elevated mRNA expression of hypothalamic H1R, neuropeptide Y (NPY), and agouti-related peptide (AgRP) compared to controls, and H1R and NPY levels were correlated with risperidone enhanced weight gain and food intake in the female juvenile rats. However, risperidone did not affect hypothalamic proopiomelanocortin (POMC) and cocaineand amphetamine-regulated transcript (CART) mRNA expression. Therefore, these results suggested that risperidone elevated appetite and body weight gain in juveniles via regulation of the hypothalamic H1R, NPY and AgRP pathways, as well as by reducing activity.

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Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats

Cited by 96 publications

References 96 publications

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways

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