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Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia
K. Holubova, M. Chvojkova, B. Hrcka Krausova, V. Vyklicky, E. Kudova, H. Chodounska, L. Vyklicky, K. Vales
Language English Country Switzerland
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
20-17945S
Grantová Agentura České Republiky
18-09296S
Grantová Agentura České Republiky
CZ.02.1.01/0.0/0.0/16_025/0007444
European Regional Development Fund project "PharmaBrain"
LO1611
"Sustainability for the National Institute of Mental Health" from the Ministry of Education, Youth and Sports of the Czech Republic
NLK
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PubMed
34356650
DOI
10.3390/biom11071026
Knihovny.cz E-resources
- MeSH
- Antipsychotic Agents pharmacology MeSH
- Bridged Bicyclo Compounds, Heterocyclic metabolism MeSH
- Behavior, Animal drug effects MeSH
- Dizocilpine Maleate pharmacology MeSH
- HEK293 Cells MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Rats, Long-Evans MeSH
- Rats, Wistar MeSH
- Pregnenolone metabolism pharmacology MeSH
- Receptors, N-Methyl-D-Aspartate antagonists & inhibitors metabolism MeSH
- Schizophrenia drug therapy metabolism MeSH
- Steroids pharmacology MeSH
- Elevated Plus Maze Test MeSH
- Reflex, Startle drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.
Institute of Physiology CAS Videnska 1083 14220 Prague Czech Republic
National Institute of Mental Health Topolova 748 25067 Klecany Czech Republic
References provided by Crossref.org
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