• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

A genetic survey of fluoxetine action on synaptic transmission in Caenorhabditis elegans.

Fluoxetine is one of the most commonly prescribed medications for many behavioral and neurological disorders. Fluoxetine acts primarily as an inhibitor of the serotonin reuptake transporter (SERT) to block the removal of serotonin from the synaptic cleft, thereby enhancing serotonin signals. While the effects of fluoxetine on behavior are firmly established, debate is ongoing whether inhibition of serotonin reuptake is a sufficient explanation for its therapeutic action. Here, we provide evidence of two additional aspects of fluoxetine action through genetic analyses in Caenorhabditis elegans. We show that fluoxetine treatment and null mutation in the sole SERT gene mod-5 eliminate serotonin in specific neurons. These neurons do not synthesize serotonin but import extracellular serotonin via MOD-5/SERT. Furthermore, we show that fluoxetine acts independently of MOD-5/SERT to regulate discrete properties of acetylcholine (Ach), gamma-aminobutyric acid (GABA), and glutamate neurotransmission in the locomotory circuit. We identified that two G-protein-coupled 5-HT receptors, SER-7 and SER-5, antagonistically regulate the effects of fluoxetine and that fluoxetine binds to SER-7. Epistatic analyses suggest that SER-7 and SER-5 act upstream of AMPA receptor GLR-1 signaling. Our work provides genetic evidence that fluoxetine may influence neuronal functions and behavior by directly targeting serotonin receptors.

Pubmed ID: 20739712

Authors

  • Kullyev A
  • Dempsey CM
  • Miller S
  • Kuan CJ
  • Hapiak VM
  • Komuniecki RW
  • Griffin CT
  • Sze JY

Journal

Genetics

Publication Data

November 10, 2010

Associated Grants

  • Agency: NIMH NIH HHS, Id: R01 MH064747-03
  • Agency: NIMH NIH HHS, Id: R01 MH064747-04
  • Agency: NIMH NIH HHS, Id: R01 MH064747-05
  • Agency: NIMH NIH HHS, Id: R01 MH083982-01
  • Agency: NIMH NIH HHS, Id: R01 MH083982-02

Mesh Terms

  • Acetylcholine
  • Animals
  • Behavior, Animal
  • Biological Assay
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Fluoxetine
  • Glutamic Acid
  • Muscle Relaxation
  • Mutation
  • Neurons
  • Receptors, Serotonin
  • Serotonin
  • Serotonin Uptake Inhibitors
  • Signal Transduction
  • Synaptic Transmission
  • gamma-Aminobutyric Acid