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

• Published in: Journal of evolutionary biochemistry and physiology 2024-09, Vol.60 (5), p.1807-1817
• Main Authors: Saulskaya, N. B., Susorova, M. A.
• Format: Article
• Language: English
• Subjects: Animal Physiology; Biochemistry; Biomedical and Life Sciences; Brain; Conditioned stimulus; D-Serine; Drug therapy; Evolutionary Biology; Experimental Papers; Fear conditioning; Footshock; Functional morphology; Glutamic acid receptors (ionotropic); Life Sciences; N-Methyl-D-aspartic acid receptors; Pain; Prefrontal cortex; Serotonin; Tonic immobility
• ISSN: 0022-0930; 1608-3202
• DOI: 10.1134/S0022093024050132

D-serine is an endogenous agonist of the glycine binding site of NMDA receptors. However, its contribution to the functional organization of the medial prefrontal cortex (mPFC) has been little studied. This work was aimed to study the involvement of mPFC D-serine 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 brain region. Using in vivo intracranial microdyalisis and HPLC analysis, we demonstrated in Sprague-Dawley rats that intra-mPFC D-serine (1 mM) infusion reduced the basal level of extracellular serotonin in this region, as well as its elevation during CFR acquisition through a paired presentation of a conditioned cue (CS+) and an inescapable electric footshock, but not during differentiation 1 through a presentation of a differentiation cue (CS–) alone. Intra-mPFC D-serine administration decreased animal freezing to CS+ (a measure of passive footshock anticipation) during the CFR acquisition and increased ambulation and the number of rearing episodes (attempts to escape footshock). A day later, this pharmacological treatment enhanced animal freezing to the potentially dangerous CS+, but not to the safe CS–. The data obtained demonstrate for the first time that D-serine-induced stimulation of the mPFC, while decreasing serotonin release in this brain region, enhances the animal’s active strategy of pain-related avoidance and suppresses the passive strategy of pain-related anticipation. This is accompanied by increased CFR acquisition and/or consolidation, but does not affect its generalization.