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Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model

K. Horska, S. Skrede, J. Kucera, G. Kuzminova, P. Suchy, V. Micale, J. Ruda-Kucerova

. 2024 ; 30 (2) : e14565. [pub] -

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24007221

Grant support
CZ.02.1.01/0.0/0.0/17_043/0009632 MEYS and the OP RDE
MUNI/A/1342/2020 Specific University Research Grant provided by Ministry of Education, Youth and Sports of the Czech Republic
MUNI/A/1342/2022 Specific University Research Grant provided by Ministry of Education, Youth and Sports of the Czech Republic
3SGA5789 SoMoPro II Programme
857560 European Union's Horizon 2020 research and innovation program
EHP-BFNU-OVNKM-3-048-2020 EEA Grants/Norway Grants
EHP-BFNU-OVNKM-4-174-01-2022 EEA Grants/Norway Grants

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.

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$a Horska, Katerina $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000181246907
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$a 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.
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