Prenatal stress‐related alterations in synaptic transmission and 5‐HT₇ receptor‐mediated effects in the rat dorsal raphe nucleus are ameliorated by the 5‐HT₇ receptor antagonist SB 269970

Abstract

Early life adversity exerts a detrimental influence on developing brain neuronal networks and its consequences may include mental health disorders. In rats, prenatal stress may lead to anxiety and depressive-like behavior in the offspring. Several lines of evidence implicated an involvement of prenatal stress in alterations of the brain serotonergic system functions, but the effects of prenatal stress on its core, the dorsal raphe nucleus (DRN), still remain incompletely understood. The present study was aimed at finding whether prenatal stress induces modifications in the glutamatergic and GABAergic inputs to DRN projection cells and whether it affects DRN 5-HT 7 receptors, which modulate activity of these synapses. Prenatal stress resulted in an increase in basal frequency of spontaneous excitatory postsynaptic currents (sEP-SCs) and in a decrease in basal frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from putative projection neurons in DRN slices ex vivo. While there were no changes in the excitability of DRN projection neurons, the 5-HT 7 receptor-mediated reduction in the sEPSC frequency and rise in the sIPSC frequency, seen in control rats, were largely absent in slices obtained from prenatally stressed rats. Repeated administration of SB 269970, a 5-HT 7 receptor antagonist, resulted in a reversal of prenatal stress-induced alterations in 5-HT 7 receptor-mediated effects on the sEPSC/sIPSC frequency. Moreover, the treatment reversed prenatal stress-induced alterations in basal excitatory transmission and partially reversed the effect of stress on basal inhibitory transmission in the DRN. How to cite this article: Sowa J, Hess G. Prenatal stress-related alterations in synaptic transmission and 5-HT 7 receptor-mediated effects in the rat dorsal raphe nucleus are ameliorated by the 5-HT 7 receptor antagonist SB 269970.

GPCR signaling: role in mediating the effects of early adversity in psychiatric disorders

“…The role of CRF receptors in the effects of early stress has been the focus of several recent reviews [98,99], and hence, we have restricted ourselves to describing the literature focused on the effects of early stress on Gs-coupled neurotransmitter receptors. A recent report indicates that in GS animals the modulatory effects of the Gscoupled 5-HT 7 receptors on the frequency of sEPSC/ sIPSCs in DRN projection neurons appears to be lost [100]. This raises the intriguing possibility that the disruption of excitatory and inhibitory input onto DRN projection neurons could directly modulate 5-HT release in key target brain regions and thus impinge on stress-response neurocircuitry and affective behavioral states.…”

“…These diverse models impinge upon a wide array of anxiety [35,48,84,107–109,112,120,125,142–149] and despair‐like behaviors [35,48,61,108,109,125,143,146,148,150–152] and also impact cognition [22,35,65,73,149,152–154], fear conditioning [35,110–112,152,155], social interaction [35,61,115,116,156–158], sensorimotor gating [38,59,60,91,93], and hallucinogen‐evoked 5‐HT 2A R‐mediated HTR [67,113,114]. Among the GPCRs reported to be dysregulated in these models of early adversity are the Gq‐, Gi‐, and Gs‐coupled receptors involved in the signaling downstream of monoamines such as serotonin (5‐HT 1A R, 5‐HT 2A R, 5‐HT 7 R) [26,38,49,67,73–78,83,84,100,107,109,110,113–115,117,120,125,146,147,149,150,159,160], DA (D 1 R, D 2 R, D 3 R, D 4 R, D 5 R) [31,101,161–164], and norepinephrine (α 2 AR, β 3 AR) [117,155], glutamate (mGluR 2 , mGluR 4 ) [38,59,60,85,91,93,113,117,151,161,165–167], endocannabinoids (CB 1 R) [21,63,162,168], and acetylcholine (M 1 ) [62], and CRFR 1 , CRFR 2 [22,37,64,84,112,142,145,154,158,169–174].…”

“…Our focus is primarily on the Gq‐coupled 5‐HT 2A R and Gi‐coupled 5‐HT 1A R pathways, and we will only briefly discuss the contributions of Gs‐coupled CRFR 1 and CRFR 2 receptors, which have been the focus of other reviews. Early stress causes alterations at multiple levels of organization spanning from molecular changes that include altered gene expression sustained via epigenetic modifications [30,37,106], cellular changes spanning from altered spine density to global dendritic architecture [46], functional and network level alterations measured predominantly via electrophysiological studies [67,73,100], and behavioral changes that are noted across a gamut of anxio‐depressive behaviors [35,107–109], fear conditioning responses [35,110–112], hallucinogen‐mediated HTR [67,113,114], sensorimotor gating [38,59,60], social approach‐avoidance behavior [35,115,116], and cognitive performance [35,65,73] (Fig. 2).…”

“…Early life blockade of 5‐HT 7 R, as well as 5‐HT 7 R knockout mice, does not exhibit the enhanced anxiety‐ and despair‐like behavior induced by PNFlx administration [125,126]. Pharmacological blockade of the 5‐HT 7 R in adulthood could remediate the GS‐evoked disruption of sEPSC/sIPSC frequency in the DRN [100]. Conversely, overexpression of 5‐HT 7 R in early life results in altered development of the PFC, resulting in increased despair‐like behavior [125].…”

Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence

“…Stress induces an increase in EPSCs and decrease in IPSCs, stimulating neuronal excitability in DRN. Blocking the 5-HT 7 receptor by SB269970 decreases cortical glutamatergic transmission and contributes to restoring balance between EPSCs and IPSCs, reducing neuronal overactivation induced by prenatal stress [ 173 ]. Directly or indirectly, 5-HT 7 receptor antagonists appear to trigger anxiolytic effects.…”