Related Experiment Video
Updated: Jun 11, 2025
Elevated Plus Maze for Mice
Published on: December 22, 2008
RNA m6A methyltransferase activator affects anxiety-related behaviours, monoamines and striatal gene expression in
Margus Kanarik1, Kristi Liiver2, Marianna Norden2,3
1Division of Neuropsychopharmacology, Institute of Chemistry, University of Tartu, Tartu, Tartumaa, Estonia.
Abstract:
Modification of mRNA by methylation is involved in post-transcriptional regulation of gene expression by affecting the splicing, transport, stability and translation of mRNA. Methylation of adenosine at N6 (m6A) is one of the most common and important cellular modification occurring in the mRNA of eukaryotes. Evidence that m6A mRNA methylation is involved in regulation of stress response and that its dysregulation may contribute to the pathogenesis of neuropsychiatric disorders is accumulating. We have examined the acute and subchronic (up to 18 days once per day intraperitoneally) effect of the first METTL3/METTL14 activator compound CHMA1004 (methyl-piperazine-2-carboxylate) at two doses (1 and 5 mg/kg) in male and female rats. CHMA1004 had a locomotor activating and anxiolytic-like profile in open field and elevated zero-maze tests. In female rats sucrose consumption and swimming in Porsolt's test were increased. Nevertheless, CHMA1004 did not exhibit strong psychostimulant-like properties: CHMA1004 had no effect on 50-kHz ultrasonic vocalizations except that it reduced the baseline difference between male and female animals, and acute drug treatment had no effect on extracellular dopamine levels in striatum. Subchronic CHMA1004 altered ex vivo catecholamine levels in several brain regions. RNA sequencing of female rat striata after subchronic CHMA1004 treatment revealed changes in the expression of a number of genes linked to dopamine neuron viability, neurodegeneration, depression, anxiety and stress response. Conclusively, the first-in-class METTL3/METTL14 activator compound CHMA1004 increased locomotor activity and elicited anxiolytic-like effects after systemic administration, demonstrating that pharmacological activation of RNA m6A methylation has potential for neuropsychiatric drug development.
Insights
The first METTL3/METTL14 activator, CHMA1004, increased locomotor activity and showed anxiolytic effects in rats. This suggests pharmacological activation of N6-methyladenosine (m6A) methylation holds promise for neuropsychiatric drug development.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- N6-methyladenosine (m6A) mRNA methylation is a key post-transcriptional regulator of gene expression.
- Dysregulation of m6A methylation is implicated in neuropsychiatric disorders and stress response.
- Developing pharmacological modulators of m6A is a promising avenue for novel therapeutics.
Purpose of the Study:
- To investigate the acute and subchronic effects of CHMA1004, a novel METTL3/METTL14 activator.
- To evaluate the behavioral and neurochemical profile of CHMA1004 in male and female rats.
- To explore the potential of targeting m6A methylation for neuropsychiatric drug development.
Main Methods:
- Administration of CHMA1004 (1 and 5 mg/kg) to male and female rats for acute and subchronic (18 days) treatment.
- Behavioral testing including open field, elevated zero-maze, Porsolt's swim test, and 50-kHz ultrasonic vocalizations.
- Measurement of extracellular dopamine levels and ex vivo catecholamine levels in brain regions.
- RNA sequencing of rat striata to analyze gene expression changes.
Main Results:
- CHMA1004 demonstrated a locomotor activating and anxiolytic-like profile.
- Female rats showed increased sucrose consumption and swimming behavior.
- No significant psychostimulant effects were observed; dopamine levels remained unchanged acutely.
- Subchronic treatment altered catecholamine levels and led to significant changes in gene expression related to neuronal function and neuropsychiatric conditions.
Conclusions:
- CHMA1004, the first METTL3/METTL14 activator, exhibits anxiolytic and locomotor-activating properties.
- Pharmacological activation of RNA m6A methylation is a viable strategy for developing treatments for neuropsychiatric disorders.
- CHMA1004's effects on gene expression suggest mechanisms relevant to depression, anxiety, and neurodegeneration.
