229. Altered corticosteroid-serotonin-dopamine interactions following maternal immune activation by lipopolysaccharide

Abstract

Abstract Background In our previous study, we found that the maternal immune activation (MIA), induced by lipopolysaccharide (LPS) administered to the gestating rats, led to decreased excitability of serotonergic neurons of the dorsal raphe nucleus (DRN) in both sexes and increased firing activity of dopaminergic neurons of the ventral tegmental area (VTA) in male offspring (Csatlosova et al Eur Neuropsychopharmacol 43:82, 2021). We hypothesized that the decreased excitability of 5-HT neurons might be due to their increased sensitivity to corticosteroids. The increased excitability of dopaminergic might in turn result from the decreased firing rate of serotonergic (5-HT) neurons. Since it was observed in males, but not in females, male and female offspring of the control and MIA dams might have different strength of 5-HT-dopamine interactions. The present study aimed to test this hypothesis. Aims & Objectives The present study aimed to examine the effect of the glucocorticoids receptor (GR) agonist, dexamethasone, on the excitability of DRN 5-HT and selective agonist of 5-HT2C receptors, MK212, on the excitability of dopaminergic neurons of the VTA in male and female offspring of the control and MIA dams. Method During days 15-19 of the gestation, female Wistar rats were subcutaneously administered LPS at increasing doses of 20-80 μg/kg. Control dams were injected with saline. In vivo electrophysiological experiments were performed in male and female offspring reaching the age of two months. Animals were anesthetized by chloral hydrate and glass electrodes were stereotaxically inserted to the DRN or VTA. Spontaneously active 5-HT or dopaminergic neurons were identified by the waveform of their action potentials and pattern of their generation. After a basal activity of a 5-HT or dopaminergic neuron was recorded for at least one minute, dexamethasone (1-5 μg/kg) or MK212 (80-320 μg/kg) was intravenously administered. The firing activity of the neurons after dexamethasone administration was expressed as mean ± standard error of mean (SEM) of their basal activity. Results Dexamethasone dose-dependently inhibited 5-HT neurons. This inhibition was stronger in the offspring of the MIA dams, compared to the controls. MK212 suppressed dopaminergic neuronal firing activity in the male and female offspring of control dams and in female offspring of the MIA dams. In male offspring of the MIA dams, dopaminergic neuronal firing activity was paradoxically increased after the activation of 5-HT2C receptors. Discussion & Conclusions The results of the current study suggest that MIA increases the inhibitory effect of corticosteroids on 5-HT neurons in both sexes and reverses the inhibitory effect of 5-HT receptors on dopaminergic neurons in males. It may explain the altered spontaneous firing activity of monoaminergic neurons in male offspring of the MIA dams, observed in our previous study. This work was supported by the grants APVV-22-0061, APVV-24-0131, VEGA-2/0045/24, and VEGA- 2/0126/26.