Transcriptional Effects of Psychoactive Drugs on Genes Involved in Neurogenesis

Abstract

Although neurogenesis is affected in several psychiatric diseases, the effects and mechanisms of action of psychoactive drugs on neurogenesis remain unknown and/or controversial. This study aims to evaluate the effects of psychoactive drugs on the expression of genes involved in neurogenesis. Neuronal-like cells (NT2-N) were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), or valproate (0.5 mM) for 24 h. Genome wide mRNA expression was quantified and analysed using gene set enrichment analysis, with the neurogenesis gene set retrieved from the Gene Ontology database and the Mammalian Adult Neurogenesis Gene Ontology (MANGO) database. Transcription factors that are more likely to regulate these genes were investigated to better understand the biological processes driving neurogenesis. Targeted metabolomics were performed using gas chromatography-mass spectrometry. Six of the eight drugs decreased the expression of genes involved in neurogenesis in both databases. This suggests that acute treatment with these psychoactive drugs negatively regulates the expression of genes involved in neurogenesis in vitro. SOX2 and three of its target genes (CCND1, BMP4, and DKK1) were also decreased after treatment with quetiapine. This can, at least in part, explain the mechanisms by which these drugs decrease neurogenesis at a transcriptional level in vitro. These results were supported by the finding of increased metabolite markers of mature neurons following treatment with most of the drugs tested, suggesting increased proportions of mature relative to immature neurons consistent with reduced neurogenesis.

Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis

“…A pluripotent cell line, NT2, was used as a model of human neurons. The use of this cell line and its ability to differentiate into post-mitotic neuronal NT2-N cells after treatment with retinoic acid (RA) has been described elsewhere [54][55][56][57]. In brief, NT2 cells were cultured in Dulbecco's modified Eagle's Medium (DMEM; Life Technologies, Melbourne, Australia) with 10% foetal bovine serum (FBS; Thermo Fisher Scientific, Melbourne, Australia) and 1% antibiotic/antimycotic solution (Life Technologies).…”

“…To quantify genome-wide messenger RNA expression, all samples were run on an Illumina HiSeq platform (HiSeq 2500 rapid 50bpSE; 1 flow cell, 2 lanes). The raw data were processed using the Deakin Genomics Centre RNA-Seq alignment and expression quantification pipeline (available at https://github.com/m-richardson/RNASeq_pipe; last accessed on 25 May 2016) as previously described [57]. Briefly, Trimmomatic v35 was used for raw read quality filtering, and adapter trimming (ILLUMINACLIP:2:30:10:4, SLIDINGWINDOW:5:20, AVGQUAL:20 MINLEN:36) [59] and STAR v2.5 (2-pass mode) was used to align data to the reference genome (Human genome version GRCh38) [60].…”

Profiling the Skeletal Muscle Proteome in Patients on Atypical Antipsychotics and Mood Stabilizers

“…FHL1 and MYH3 have been shown to have decreased RNA levels in skeletal muscle following the infusion of olanzapine in rat models [ 72 ]. FABP3 gene expression may also be influenced by antipsychotics, lithium, and valproic acid [ 73 ]. Furthermore, HSPA6/7 are chaperone proteins of the heat shock family, which may enhance metabolic profiles in skeletal muscle and serve as a defense system against insulin resistance and T2D [ 74 ].…”

Effect of Escitalopram on the Number of DCX-Positive Cells and NMUR2 Receptor Expression in the Rat Hippocampus under the Condition of NPSR Receptor Blockade

“…Neuropsychiatric medications may distinctly affect canonical adult neurogenesis in animal models [ 9 , 34 , 35 ]. Most of them can cross the blood-brain barrier and modulate some signalling pathways within neural stem cell niches.…”