Related Experiment Video

Updated: Nov 28, 2025

Rapid In Situ Hybridization using Oligonucleotide Probes on Paraformaldehyde-prefixed Brain of Rats with Serotonin Syndrome

Rapid In Situ Hybridization using Oligonucleotide Probes on Paraformaldehyde-prefixed Brain of Rats with Serotonin Syndrome

Published on: September 23, 2015

Genetic Background Underlying 5-HT_1A Receptor Functioning Affects the Response to Fluoxetine

Elena M Kondaurova¹, Alexander Ya Rodnyy¹, Tatiana V Ilchibaeva¹

¹Department of Behavioral Neurogenomics, Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, Novosibirsk 630090, Russia.

International Journal of Molecular Sciences

|November 25, 2020

Abstract:

The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73-110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT_1A receptors to chronic 8-OH-DPAT administration and higher 5-HT_1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT_1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT_1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT_1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.

Insights

Genetic background significantly impacts antidepressant response. Recombinant mice with a specific chromosome 13 fragment showed antidepressant resistance, unlike controls, highlighting personalized medicine needs.

Area of Science:

Neuroscience
Pharmacology
Genetics

Background:

Genetic background influences drug sensitivity, a key factor in personalized medicine.
Recombinant B6-M76C mice possess a specific chromosomal fragment affecting serotonin 5-HT1A receptor sensitivity and expression.
These mice exhibit altered 5-HT1A receptor function compared to control B6-M76B mice.

Purpose of the Study:

To investigate the impact of chronic fluoxetine treatment on the behavior and brain serotonin system of recombinant B6-M76C mice.
To compare the effects of fluoxetine in B6-M76C mice with those in control B6-M76B mice.
To explore the role of genetic background in antidepressant sensitivity and resistance.

Main Methods:

Chronic administration of fluoxetine (20 mg/kg, 14 days, i.p.) to B6-M76B and B6-M76C mice.
Behavioral assessment using the forced swim test.
Analysis of serotonin 5-HT1A receptor mRNA and protein levels.
Measurement of tryptophan hydroxylase-2 (TPH2) and serotonin transporter (SERT) gene and protein expression.
Quantification of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in brain regions.

Main Results:

Fluoxetine induced pro-depressive effects in B6-M76C mice, unlike B6-M76B mice.
In B6-M76C mice, fluoxetine decreased 5-HT1A receptor mRNA and protein, and increased Freud-1 protein.
Fluoxetine altered TPH2 and SERT expression and 5-HT/5-HIAA levels differently across brain regions in both mouse lines.

Conclusions:

Genetic background variations significantly alter sensitivity to selective serotonin reuptake inhibitor (SSRI) antidepressants like fluoxetine.
The study provides evidence for disrupted 5-HT1A autoreceptor functioning in B6-M76C mice.
B6-M76C mice serve as a valuable model for studying antidepressant resistance.

Read full analysis

Keywords:

5-HT1A receptor Freud-1 SSRI antidepressants resistance fluoxetine mice serotonin

More Related Videos

Applying Stereotactic Injection Technique to Study Genetic Effects on Animal Behaviors

Applying Stereotactic Injection Technique to Study Genetic Effects on Animal Behaviors

Published on: May 10, 2015

The Forced Swim Test as a Model of Depressive-like Behavior

The Forced Swim Test as a Model of Depressive-like Behavior

Published on: March 2, 2015

Related Concept Videos

Human Genetics

Human Genetics

Human genetics provides a profound framework for understanding the interplay between genetic predispositions and human psychology. At the heart of this discipline lies the study of how genes influence physical traits, behaviors, and susceptibility to diseases. Each person carries a unique genetic code that subtly or significantly shapes their psychological and behavioral landscape.
The complex relationship between genetics and psychology is observable through common biological components such...

Antidepressant Drugs: MAOIs and Other Agents

Antidepressant Drugs: MAOIs and Other Agents

Atypical antidepressants, including bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone (Serzone), trazodone (Desyrel), and vilazodone (Viibryd), offer unique mechanisms of action. Bupropion weakly inhibits dopamine and norepinephrine reuptake, aiding depression treatment and smoking cessation, with a low risk of sexual dysfunction. Mirtazapine enhances serotonin and norepinephrine neurotransmission, leading to sedation, increased appetite, and weight gain. As a result, it helps treat...

G-protein Coupled Receptors

G-protein Coupled Receptors

G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.

Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance

Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance

The elimination half-life and drug clearance of drugs following nonlinear kinetics can vary with dosage. The Michaelis-Menten parameters and drug concentration influence these factors. As the dose increases, the elimination half-life tends to lengthen, resulting in a reduction in clearance and a disproportionately larger area under the curve. The total clearance can be derived from the Michaelis-Menten equation for drugs following a one-compartment model.
A study on guinea pigs examined the...

Drugs Affecting GI Tract Motility: Serotonin Receptor Agonists

Drugs Affecting GI Tract Motility: Serotonin Receptor Agonists

Serotonin, a crucial neurotransmitter synthesized by enterochromaffin cells, plays a cardinal role in regulating gastrointestinal (GI) motility. With over 90% of the body's total serotonin in the GI tract, its influence on digestive processes is profound. Serotonin is swiftly released upon various stimuli, such as food boluses or certain drugs, triggering intrinsic sensory neurons in the myenteric plexus and extrinsic vagal and spinal sensory neurons. This leads to the activation of the...

Drugs Affecting Neurotransmitter Release or Uptake

Drugs Affecting Neurotransmitter Release or Uptake

Certain drugs can affect how neurotransmitters called catecholamines, are released or taken back up in the adrenergic neuron. They can have different effects on the body's sympathetic transmission. Reserpine, a natural compound found in the Rauwolfia shrub, blocks a transporter called vesicular monoamine transporter (VMAT), which leads to a buildup of catecholamines in the cell and reduces sympathetic transmission. Another drug called guanethidine works in multiple ways, including blocking...

Articles linked to this work by shared authors, journal, and citation graph.

Cross-Species Triage of SERT-Oriented Polyheteroaryl Candidates Prioritizes AD20/UtIA-0108 as an Early Neuroactive Candidate.

Current issues in molecular biology·2026

The olfactory epithelium as a gateway for bloodborne nanoparticles to the central nervous system.

Biomaterials science·2025

Brain-Derived Neurotrophic Factor (BDNF) in the Frontal Cortex Enhances Social Interest in the BTBR Mouse Model of Autism.

Biochemistry. Biokhimiia·2024

Key Enzymes of the Serotonergic System - Tryptophan Hydroxylase 2 and Monoamine Oxidase A - In the Brain of Rats Selectively Bred for a Reaction toward Humans: Effects of Benzopentathiepin TC-2153.

Biochemistry. Biokhimiia·2024

Serotonin Receptors as a Potential Target in the Treatment of Alzheimer's Disease.

Biochemistry. Biokhimiia·2024

In Vitro and In Vivo Chaperone Effect of (R)-2-amino-6-(1R, 2S)-1,2-dihydroxypropyl)-5,6,7,8-tetrahydropterin-4(3H)-one on the C1473G Mutant Tryptophan Hydroxylase 2.

Biomolecules·2023

See all related articles