Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model
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Published on: June 29, 2018
Katerina Horska1, Silje Skrede2,3, Jan Kucera4,5
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Brno, Czech Republic.
Aim:
Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders.
Methods:
In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats.
Results:
Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM.
Conclusion:
Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.
Insights
Second-generation antipsychotics cause metabolic issues. Using a neurodevelopmental animal model, this study found that these drugs, particularly olanzapine, worsen metabolic disturbances in rats with schizophrenia-like traits, highlighting the need for better models.
Area of Science:
- Neuroscience
- Pharmacology
- Metabolic Disorders
Background:
- Second-generation antipsychotics are linked to adverse metabolic effects and increased cardiovascular mortality.
- Preclinical models are crucial for understanding antipsychotic-induced metabolic dysfunction.
- Existing models often use healthy animals, potentially underestimating metabolic risks in individuals with psychotic disorders.
Purpose of the Study:
- To investigate the dysmetabolic effects of olanzapine and haloperidol in a neurodevelopmental animal model of schizophrenia.
- To assess the impact of prenatal methylazoxymethanol acetate (MAM) exposure on metabolic responses to antipsychotics.
Main Methods:
- Prenatal administration of methylazoxymethanol acetate (MAM) to Sprague-Dawley rats at gestational day 17 to induce a schizophrenia-like neurodevelopmental model.
- Acute treatment with olanzapine and haloperidol in female MAM-exposed and non-exposed rats.
- Examination of serum lipid profiles to assess metabolic disturbances.
Main Results:
- Prenatally MAM-exposed rats exhibited inherent lipid disturbances.
- Olanzapine treatment led to pronounced serum lipid profile alterations in MAM-exposed rats, suggesting disruption of a delicate metabolic balance.
- Olanzapine induced more significant metabolic dysfunctions than haloperidol in both MAM-exposed and non-exposed rats, aligning with clinical observations.
Conclusions:
- Female rats exposed to MAM prenatally display metabolic vulnerability.
- Findings from healthy animal models likely underestimate the metabolic dysfunction associated with antipsychotic treatment.
- Neurodevelopmental models are valuable for studying antipsychotic-induced metabolic disturbances, warranting increased attention in experimental psychopharmacology.
