Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia

Biomolecules

Eva Kudova¹  Hana Chodounska¹  Vojtech Vyklicky²  Barbora Hrcka Krausova²  Ladislav Vyklicky²  Kristina Holubova³  Karel Vales³  Marketa Chvojkova³ 

[1] Institute of Organic Chemistry and Biochemistry CAS, Flemingovo namesti 542/2, 16000 Prague, Czech Republic;Institute of Physiology CAS, Videnska 1083, 14220 Prague, Czech Republic;National Institute of Mental Health, Topolova 748, 25067 Klecany, Czech Republic;

关键词: neurosteroids;    schizophrenia;    MK-801;    cognition;    anxiety;    stress;   

DOI  :  10.3390/biom11071026

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown