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

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Abstract

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.

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N. B. Saulskaya

Pavlov Institute of Physiology, Russian Academy of Sciences

Author for correspondence.
Email: saulskayanb@infran.ru
Russian Federation, Saint Petersburg

M. A. Susorova

Pavlov Institute of Physiology, Russian Academy of Sciences

Email: saulskayanb@infran.ru
Russian Federation, Saint Petersburg

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2. Fig. 1. Experimental design. (CS+) – conditioned signal; (CS-) – differentiation signal; US – unconditioned stimulus (electrocutaneous stimulation).

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3. Fig. 2. Horizontal motor activity, crossings (Ambulation, crossing) and the number of rearings (Rearing) in the open field test in rats before the introduction of D-serine into the MPC (Before D-Serine) and in animals without the introduction of D-serine (No Treatment). No significant differences were found, Student's t-test.

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4. Fig. 3. Changes in the level of extracellular serotonin in the mCBC during the development of URS (CFR Training) and differentiation 1 (Differentiation 1) in rats exposed (D-Serine + CFR Training) and not exposed (CFR Training) to the introduction of D-serine into the mCBC. The development of URS led to an increase in the level of serotonin in the mCBC (chi-square = 57.5, k = 13, p < 0.001, Friedman criterion, one-way analysis of variance). Administration of 1 mM D-serine decreased the basal serotonin level in the mCBC (F(8, 64) = 27.4, p < 0.001, F-test, one-way ANOVA) and, against this background, reduced its increase during the development of the URS (F(13, 266) = 3.8, p < 0.001, F-test, two-way ANOVA). X-axis – time, min; Y-axis – extracellular serotonin level, % of the background; scatter on the graph – error of the mean; arrows – behavioral tests; horizontal line – period of D-serine administration. * – p < 0.05 – when compared with the background (Newman–Keels test); + – p < 0.05 – for intergroup comparison (Newman–Keels test); # – p < 0.05 – for comparison with serotonin levels altered by the administration of D-serine before the test (Newman–Keels test).

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5. Fig. 4. (a) Duration of freezing to sound signals (CS+, CS-, s) and (b) in intersignal intervals (CS+ test, CS- test, s) during CFR Training and Differentiation 1 in rats with 1 mM D-Serine administered to the mC and in animals not subjected to the drug (No Treatment). D-serine administration reduced freezing to CS+ and in intersignal intervals during CFR Training. + – p = 0.04, t = 2.3; +++ – p < 0.001, t = 3.9 – in intergroup comparison (Student’s t-test).

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6. Fig. 5. Increase in horizontal locomotor activity (Ambulation, crossing lines) and rearing (a) during CFR Training (b) but not during Differentiation 1 in rats with D-Serine administration to the mCV compared to rats without D-serine administration (No Treatment). ++ – p = 0.02 (Mann–Whitney test); *** – p < 0.001, t = 4.2 (Student’s t-test) – for intergroup comparison. Other designations as in Fig. 3.

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7. Fig. 6. (a) Duration of freezing to sound signals (CS- or CS+, s) and (b) Duration of freezing in intersignal intervals (CS+ test, CS- test, s) during differentiation 2 (Differentiation 2) and during CFR testing in rats previously exposed (After D-Serine) and not exposed (No Treatment) to the introduction of 1 mM D-serine into the mMC. The introduction of D-serine increased freezing to CS+ (+ – p = 0.01, t = 2.7, Student's t-test) and in intersignal intervals & – p = 0.004, (Mann-Whitney test) during CFR testing. * – p < 0.05, (Student’s t-test) and # – p < 0.05 (Mann–Whitney test) – when comparing between tests.

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8. Fig. 7. (a) – Duration of stay, s, (b) – Horizontal motor activity (Ambulation), crossings, (c) – Standing/hanging in open (Open arms) and closed (Closed arms) arms of the plus maze in rats previously exposed (After D-Serine) and not exposed (No Treatment) to the introduction of 1 mM D-serine into the MPC. No significant differences were found, Mann-Whitney criterion.

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9. Fig. 8. Proposed mechanism of D-serine influence on serotonin release in mPFC and on animal behavior during URS development and testing, based on the results of this article and on the analysis of Maier [15]. mPFC – mPFC, DRN – dorsal raphe nucleus, GLU – glutamate, GABA – GABA, 5HT – serotonin, NMDAr – NMDA receptor, CFR formation – URS development, + – activation, – – inhibition. Black arrow – decrease in serotonin level in response to inescapable stress.

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