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Published on: July 9, 2016
Evidence that genetic variation in 5-HT transporter expression is linked to changes in 5-HT2A receptor function
K A Jennings1, W J Sheward, A J Harmar
1University Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, UK. katie.jennings@pharm.ox.ac.uk
Neuropharmacology
|February 5, 2008
Summary
Variability in serotonin transporter (5-HTT) gene expression influences 5-HT(2A) receptor function. Elevated 5-HTT expression increases 5-HT(2A) receptor activity, potentially due to reduced synaptic serotonin availability.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Human population studies link 5-HTT gene expression variability to behavioral phenotypes.
- Mechanisms underlying this association, possibly involving 5-HT receptor signaling, remain unclear.
Purpose of the Study:
- To investigate if altered 5-HTT expression impacts 5-HT(2A) receptor function using a novel transgenic mouse model.
- To explore the relationship between 5-HTT levels, 5-HT(2A) receptor activity, and serotonin availability.
Main Methods:
- Utilized 5-HTT overexpressing transgenic mice and wildtype littermates.
- Administered 5-HT(2) receptor agonist DOI and antagonist MDL 100907.
- Measured regional brain mRNA expression of c-fos and Arc genes.
- Assessed head twitch responses.
- Quantified 5-HT(2A) receptor binding sites and mRNA via autoradiography and in situ hybridization.
- Determined regional brain 5-HT levels.
- Induced 5-HT depletion using p-chlorophenylalanine in wildtype mice.
Main Results:
- DOI induced greater c-fos and Arc mRNA expression and more head twitches in 5-HTT overexpressing mice compared to wildtypes.
- No significant differences in 5-HT(2A) receptor binding or mRNA levels were observed between genotypes.
- Transgenic mice exhibited lower regional brain 5-HT levels.
- 5-HT depletion in wildtype mice enhanced the head twitch response to DOI.
Conclusions:
- Elevated 5-HTT expression is associated with increased 5-HT(2A) receptor function.
- This functional enhancement may be mediated by reduced synaptic 5-HT availability.
- Variability in 5-HTT expression could be a key factor modifying 5-HTT-linked behavioral phenotypes through altered 5-HT(2A) receptor function.
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