<i>In vitro</i>effect of antipsychotics on brain energy metabolism parameters in the brain of rats

Scaini, Giselli; Rochi, Natália; Morais, Meline O. S.; Maggi, Débora D.; De-Nês, Bruna Tramontin; Quevedo, Joao L De; Streck, Emílio L.

doi:10.1111/j.1601-5215.2012.00650.x

Cited by 7 publications

(4 citation statements)

References 57 publications

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“…In vivo evidence of acute CLZ effects on neurometabolite levels is sparsely documented, although we know that chronic clozapine treatment does effect levels of glutamate, glutamine, creatine, NAA+NAAG and other metabolites (McLoughlin et al, 2009). Likewise, CLZ is without effect on the activity of nGCP II, the enzyme that catabolizes NAAG to glutamate (Flores and Coyle, 2003), or creatine kinase, the enzyme that catabolizes creatine to phosphocreatine (Assis et al, 2007; Scaini et al, 2013). The effects of CLZ on glutamate levels and glutamate signaling are particularly ambiguous.…”

Section: Discussionmentioning

confidence: 99%

The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces in vivo Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels

et al. 2019

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Chemogenetic studies with the ligand clozapine N-oxide (CNO) are predicated upon the assumption that CNO is devoid of actions at natural neuroreceptors. However, recent evidence shows that CNO may be converted back to clozapine (CLZ) in vivo , which could yield plasma concentrations that may be sufficient to occupy inter alia dopamine D 2/3 and serotonin 5HT 2A receptors in living brain. To test this phenomenon, we measured striatal dopamine D 2/3 receptor occupancy with [ 18 F]fallypride PET and serotonin 5HT 2A occupancy ex vivo using [ 18 F]MH.MZ. We found a CNO dose-dependent effect on the availability of both neuroreceptor sites. In parallel MR spectroscopy experiments, we found that CNO reduced creatine + phosphcreatine (Cr+PCr) and increased N -acetylaspartate + N -acetylaspartylglutamate (NAA+NAAG) signals in the prefrontal cortex, and also reduced the glutamate signal in dorsal striatum, with peak effect at 2 mg/kg. Thus, our findings suggest that conversion of CNO to CLZ in living rats imparts significant occupancy at endogenous neuroreceptors and significant changes to neurometabolite levels.

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Section: Discussionmentioning

confidence: 99%

The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces in vivo Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels

et al. 2019

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“…Our study focuses on olanzapine, which is known to affect lipid metabolism (Spertus et al, 2018 ). Olanzapine is reported to increase the activity of mitochondrial respiratory chain complexes (Scaini et al, 2013 ), which works to generate adenosine triphosphate (ATP). Decreased ATP levels have been reported in the frontal lobes in antipsychotic-free patients with schizophrenia (Volz et al, 2000 ).…”

Section: Discussionmentioning

confidence: 99%

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication

Tani,

Moxon-Emre,

Forde

et al. 2023

Brain Imaging and Behavior

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Background The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. Methods Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. Results Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25–1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71–2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. Conclusions Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

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“…Mitochondrial dysfunction is highly implicated in obesity (Bournat and Brown, 2010; Holmström et al, 2012; Raffaella et al, 2008; Ritov et al, 2010) and olanzapine inhibits mitochondrial complex IV (cytochrome C oxidase) in neurons in vitro (Scaini et al, 2013). There is also evidence that the GLP-1 system can alter mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

et al. 2021

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Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that prevents metabolic side effects of the antipsychotic drugs (APDs) olanzapine and clozapine through unknown mechanisms. Aim: This study aimed to investigate the effect of chronic APD and liraglutide co-treatment on key neural and peripheral metabolic signals, and acute liraglutide co-treatment on clozapine-induced hyperglycaemia. Methods: In study 1, rats were administered olanzapine (2 mg/kg), clozapine (12 mg/kg), liraglutide (0.2 mg/kg), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle for six weeks. Feeding efficiency was examined weekly. Examination of brain tissue (dorsal vagal complex (DVC) and mediobasal hypothalamus (MBH)), plasma metabolic hormones and peripheral (liver and kidney) cellular metabolism and oxidative stress was conducted. In study 2, rats were administered a single dose of clozapine (12 mg/kg), liraglutide (0.4 mg/kg), clozapine + liraglutide co-treatment or vehicle. Glucose tolerance and plasma hormone levels were assessed. Results: Liraglutide co-treatment prevented the time-dependent increase in feeding efficiency caused by olanzapine, which plateaued by six weeks. There was no effect of chronic treatment on melanocortinergic, GABAergic, glutamatergic or endocannabionoid markers in the MBH or DVC. Peripheral hormones and cellular metabolic markers were unaltered by chronic APD treatment. Acute liraglutide co-treatment was unable to prevent clozapine-induced hyperglycaemia, but it did alter catecholamine levels. Conclusion: The unexpected lack of change to central and peripheral markers following chronic treatment, despite the presence of weight gain, may reflect adaptive mechanisms. Further studies examining alterations across different time points are required to continue to elucidate the mechanisms underlying the benefits of liraglutide on APD-induced metabolic side effects.

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In vitroeffect of antipsychotics on brain energy metabolism parameters in the brain of rats

Abstract: In this context, if the hypothesis that metabolism impairment is involved in the pathophysiology of neuropsychiatric disorders is correct and these results also occur in vivo, we suggest that olanzapine may reverse a possible diminution of metabolism.

Cited by 7 publications

References 57 publications

The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces in vivo Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels

The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces in vivo Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication

Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

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