5-HT 2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress

Abstract

Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A) receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS) on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC) and hippocampus in 5-HT2A receptor knockout (5-HT2A−/−) and wild-type mice of both sexes. While 5-HT2A−/− male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT2A−/− female mice with a hyperlipidemic baseline phenotype. 5-HT2A−/− male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2), trophic factors (Bdnf, Igf1) and immediate early genes (IEGs) (Arc, Fos, Fosb, Egr1-4) in the PFC and hippocampus were altered in 5-HT2A−/− mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic.

5-HT2A receptor loss does not alter acute fluoxetine-induced anxiety and exhibit sex-dependent regulation of cortical immediate early gene expression

“…Interestingly, while we did observe the previously reported baseline anxiolytic behavioral response in 5-HT 2A −/− male and female mice (Supplementary Figure S1) [10,14], the vehicle-treated 5-HT 2A −/− cohorts used for the acute Jund. We also performed qpCR analysis for the Htr2a to further confirm our genotyping results.…”

“…Further, we addressed the degree of neural activation evoked by acute Flx in the paraventricular nucleus (PVN) of the hypothalamus and the prefrontal cortex (PFC) in 5-HT 2A −/− and WT mice, and gene expression of several activity-regulated, immediate early genes (IEGs) in the PFC. 5-HT 2A −/− mice have been previously reported to exhibit a baseline anxiolytic phenotype [10,14], higher firing rates of dorsal raphe 5-hydroxytryptamine or serotonin (5-HT) neurones [15] and also to display treatment resistance to chronic Flx administration [16]. Our results reveal that the anxiogenic effects of acute Flx treatment, as well as the enhanced serum corticosterone levels are unaltered in 5-HT 2A −/− mice of both sexes.…”

“…Serotonin 2A receptor (5-HT 2A ) knockout mice (5-HT 2A −/− ) [10] and wild-type (WT) littermate controls of both sexes (4-7 months) were maintained on a 129S6/SvEv background, and group housed on a 12-h normal light-dark cycle, with access to food and water ad libitum in the Tata Institute of Fundamental Research (TIFR) animal house facility. Genotypes were confirmed using PCR analysis as described previously [14]. All experimental procedures followed the guidelines of the Committee for Supervision and Care of Experimental Animals (CPCSEA), Government of India, and were approved by the TIFR Institutional Animal Ethics committee in accordance with the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publication No.…”

“…Animals were assessed for anxiety-like response on the OFT as described previously [14]. Briefly, mice were placed in one corner of the arena and allowed to explore the arena for 10 min under dim light conditions.…”

“…−/− mice exhibit acute Flx-induced enhanced anxiety-like behavior in the OFT 5-HT 2A receptor knockout (5-HT 2A −/− ) mice have been reported to exhibit reduced anxiety-like behavior across both sexes (Supplementary Figure S1) [10,14]. Acute Flx treatment is known to enhance anxiety-like behavioral responses [3].…”