Modelling olanzapine-induced weight gain in rats

Zwaal, Esther M. van der; Janhunen, Sanna; Fleur, Susanne E. la; Adan, Roger A.H.

doi:10.1017/s146114571300093x

Cited by 35 publications

(27 citation statements)

References 115 publications

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“…The female rats were used in this study, because the SGAinduced weight gain model has been consistently established and validated in female rats in our and other laboratories [27,[63][64][65], while it could not be consistently modelled in male rodents [66]. Clinically, it is also a common observation that female patients have a much higher risk than males for SGA-induced weight gain and other metabolic side-effects [67][68][69][70].…”

Section: Discussionmentioning

confidence: 99%

Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways

Liu¹,

Lian

et al. 2015

Pharmacological Research

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Second-generation antipsychotics including olanzapine are associated with weight gain, dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with betahistine (a histamine H1 receptor agonist/H3 receptor antagonist) is effective in controlling olanzapine-induced weight gain. In the present study, we investigate whether co-treatment with betahistine is able to prevent dyslipidemia induced by chronic olanzapine treatment and the underlying mechanisms. Female rats were orally administered with olanzapine (1 mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2) olanzapine-only (1 mg/kg, t.i.d.), (3) betahistine-only (9.6 mg/kg, t.i.d.), and (4) olanzapine and betahistine (O+B) co-treatment. After completing treatment, hepatic mRNA expression was measured by qRT-PCR, while the protein levels were detected by western blot. In our study, olanzapine-only treatment significantly increased triglyceride accumulation and non-esterified fatty acids (NEFA), and upregulated mRNA expression of sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1 protein expression but an increased expression of peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with olanzapine-only treatment. In addition, olanzapine significantly increased hepatic histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that betahistine could act on hepatic H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate olanzapine-induced dyslipidemia in rats.

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Section: Discussionmentioning

confidence: 99%

Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways

Liu¹,

Lian

et al. 2015

Pharmacological Research

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“…In terms of energy expenditure, APDs such as olanzapine reduce locomotor activity in rodent models, which further disrupts the balance between energy intake and consumption and leads to weight gain (van der Zwaal et al, 2014 ). Moreover, these olanzapine-induced decreases in locomotor activity occur at doses that do not affect eating behavior (Weston-Green et al, 2011 ).…”

Section: Apd-induced Effects On Appetite and Energy Consumptionmentioning

confidence: 99%

“…Moreover, these olanzapine-induced decreases in locomotor activity occur at doses that do not affect eating behavior (Weston-Green et al, 2011 ). It has been suggested that APDs' sedative properties play an important role in causing this diminished energy consumption (van der Zwaal et al, 2014 ). Consistent with this, there is significant incidence of somnolence in people treated with many second-generation APDs (Gao et al, 2008 ).…”

Section: Apd-induced Effects On Appetite and Energy Consumptionmentioning

confidence: 99%

Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia

et al. 2017

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For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs) which on their own are also strongly associated with metabolic side effects. The combination of APD-induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naïve patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control.

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“…In rodents, the metabolic effects of APD treatment appear to be more robust in females [See review (Van Der Zwaal et al 2014)]. The preclinical findings in female adolescent rodents are in line with the clinical reports that adolescent patients are susceptible to the metabolic effects of APDs.…”

Section: Metabolic Effects Of Adolescent Apd Administrationsupporting

confidence: 62%

Evaluating long-term consequences of adolescent antipsychotic exposure

Moe¹

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Antipsychotic drugs (APDs) are being used increasingly to treat a variety of conditions in adolescence. Accordingly there has been a dramatic increase in the prescription of APDs to adolescents over the past twenty years. Adolescence is an important postnatal developmental period in which major maturation changes occur in both brain structures and multiple neurotransmitter systems. Therefore, adolescence may represent a period of sensitivity to environmental perturbations including exposure to such pharmacological agents. The specific neurobiological consequences of APDs on the adolescent brain are however still poorly understood. The aim of the work presented in this thesis is to investigate how APD administration in adolescence can affect the immature adolescent brain, using a rodent model of adolescence.In this thesis, I examined chronic risperidone treatment (1.3 mg/kg/day for 21-22 days) in adolescent rats (postnatal day (PND) 36-PND56/57) with respect to short-and long-term neurobiological changes. Short-term alterations were measured either during or proximal to chronic treatment. Long-term effects were measured after a lengthy drug-free interval of 36 -60 days.Risperidone-induced neurobiological effects in adolescents were compared with those in adult rats (PND80-PND100/101) treated with the same risperidone regimen. Risperidone was chosen for detailed examination given this is the atypical APD that is most commonly prescribed to adolescents in the clinic. Behavioural effects were assessed using two well-validated tests for APD action, namely suppression of the conditioned avoidance response (CAR) and the horizontal bar test for catalepsy. Risperidone-induced changes in brain structures and metabolism of the nucleus accumbens (NAc) were examined with clinical comparable methods namely magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ( 1 H MRS), respectively.Neurochemical alterations and gene expression in the NAc and the striatum were assessed with high performance liquid chromatography (HPLC) and real-time polymerase chain reaction respectively.My data reveal that, during chronic risperidone treatment, adolescent rats were less sensitive to risperidone-induced increases in catalepsy (when tested in horizontal bar test) and escape failures (when tested in CAR paradigm), both of which are striatum-dependent behaviours. By contrast, adult rats were observed to develop a progressive increase in these behaviours during chronic risperidone treatment. Accompanying these behavioural findings, increased levels of dopamine metabolites were observed selectively in the striatum of rats treated with risperidone in adolescence.Increased dopamine metabolites represent increased turnover of dopamine and/or increased dopamine availability, which both suggest increased dopaminergic signalling. Increased dopamine neurotransmission in adolescent-treated rats may overcome the behavioural effects of dopaminergic blockade by risperidone. When assessed after an equivalent drug-free interval o...

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Modelling olanzapine-induced weight gain in rats

Cited by 35 publications

References 115 publications

Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways

Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways

Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia

Evaluating long-term consequences of adolescent antipsychotic exposure

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