D-Serine Reduces Extracellular Serotonin Levels in the Medial Prefrontal Cortex and Enhances Fear Response Formation in Rats

D-serine is an endogenous agonist of the glycine binding siteof NMDA receptors. However, its contribution to the functional organizationof the medial prefrontal cortex (mPFC) has been little studied.This work was aimed to study the involvement of mPFC D-serine inthe formation and generalization of the conditioned fear response(CFR, a fear model), as well as in the regulation of serotonin releasein this brain region. Using in vivo intracranial microdyalisis andHPLC analysis, we demonstrated in Sprague-Dawley rats that intra-mPFCD-serine (1 mM) infusion reduced the basal level of extracellularserotonin in this region, as well as its elevation during CFR acquisitionthrough a paired presentation of a conditioned cue (CS+) and aninescapable electric footshock, but not during differentiation 1through a presentation of a differentiation cue (CS–) alone. Intra-mPFCD-serine administration decreased animal freezing to CS+ (a measureof passive footshock anticipation) during the CFR acquisition andincreased ambulation and the number of rearing episodes (attemptsto escape footshock). A day later, this pharmacological treatmentenhanced animal freezing to the potentially dangerous CS+, but notto the safe CS–. The data obtained demonstrate for the first timethat D-serine-induced stimulation of the mPFC, while decreasingserotonin release in this brain region, enhances the animal’s activestrategy of pain-related avoidance and suppresses the passive strategyof pain-related anticipation. This is accompanied by increased CFRacquisition and/or consolidation, but does not affect its generalization.