D-serine reduces extracellular serotonin level in the medial prefrontal cortex and enhances the formation of fear response in rats

D-serine is an endogenous agonist of the glycine site of NMDA receptors. However, its contribution to the medial prefrontal cortex (mPFC) functions has been little studied. The purpose of the work was to study the involvement of D-serine in the mPFC in the formation and generalization of the conditioned fear response (CFR – a fear model), as well as in the regulation of serotonin release in this area. In Sprague-Dawley rats by means of in vivo microdyalisis and HPLC analysis, we showed that the intra-mPFC infusion of D-serine (1 mM) reduces the basal level of extracellular serotonin in this area and decreases its rise during CFR acquisition (pared presentation of a conditioned cue (CS+) and inescapable footshock but not during differentiation 1 (presentation of a differentiation cue (CS-) alone).The intra-mPFC D-serine infusion reduced animals’ freezing to CS+ (a measure of passive footshock anticipation) during the CFR acquisition and increased ambulation and the number of rearing (attempts to escape footshock). This pharmacological treatment, a day after it, increased animals’ freezing to the potentially dangerous CS+, but did not affect freezing to the safe CS-. The data obtained indicate for the first time that, with a decrease in the release of serotonin in the mPFC, stimulation of the mPFC by D-serine enhances the animals’ active strategy of avoiding shock and suppresses the passive strategy of anticipating it. This is accompanied by increased acquisition and/or consolidation of the CFR, but does not affect its generalization.