Pregnanolone glutamate, a novel use-dependent NMDA receptor inhibitor, exerts antidepressant-like properties in animal models

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Authors

HOLUBOVA Kristina NEKOVAROVA Tereza PISTOVČÁKOVÁ Jana ŠULCOVÁ Alexandra STUCHLIK Ales VALES Karel

Year of publication 2014
Type Article in Periodical
Magazine / Source Frontiers in Behavioral Neuroscience
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://journal.frontiersin.org/Journal/10.3389/fnbeh.2014.00130/full
Doi http://dx.doi.org/10.3389/fnbeh.2014.00130
Field Pharmacology and pharmaceutical chemistry
Keywords pregnanolone glutamate; NMDAR; anxiolytic-like properties; antidepressant-like properties
Attached files
Description A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3alfa5beta-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3alfaC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders.
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