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

Andrey Kullyev, Catherine M. Dempsey, Sarah Miller, Chih Jen Kuan, Vera M. Hapiak, Richard W. Komuniecki, Christine T. Griffin, Ji Ying Sze

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)929-941
Number of pages13
JournalGenetics
Volume186
Issue number3
DOIs
StatePublished - Nov 2010

Fingerprint

Fluoxetine
Caenorhabditis elegans
Synaptic Transmission
Serotonin
Serotonin Plasma Membrane Transport Proteins
Serotonin Receptors
Surveys and Questionnaires
Neurons
AMPA Receptors
Nervous System Diseases
GTP-Binding Proteins
gamma-Aminobutyric Acid
Acetylcholine
Glutamic Acid
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

Kullyev, A., Dempsey, C. M., Miller, S., Kuan, C. J., Hapiak, V. M., Komuniecki, R. W., ... Sze, J. Y. (2010). A genetic survey of fluoxetine action on synaptic transmission in Caenorhabditis elegans. Genetics, 186(3), 929-941. https://doi.org/10.1534/genetics.110.118877

A genetic survey of fluoxetine action on synaptic transmission in Caenorhabditis elegans. / Kullyev, Andrey; Dempsey, Catherine M.; Miller, Sarah; Kuan, Chih Jen; Hapiak, Vera M.; Komuniecki, Richard W.; Griffin, Christine T.; Sze, Ji Ying.

In: Genetics, Vol. 186, No. 3, 11.2010, p. 929-941.

Research output: Contribution to journalArticle

Kullyev, A, Dempsey, CM, Miller, S, Kuan, CJ, Hapiak, VM, Komuniecki, RW, Griffin, CT & Sze, JY 2010, 'A genetic survey of fluoxetine action on synaptic transmission in Caenorhabditis elegans', Genetics, vol. 186, no. 3, pp. 929-941. https://doi.org/10.1534/genetics.110.118877
Kullyev A, Dempsey CM, Miller S, Kuan CJ, Hapiak VM, Komuniecki RW et al. A genetic survey of fluoxetine action on synaptic transmission in Caenorhabditis elegans. Genetics. 2010 Nov;186(3):929-941. https://doi.org/10.1534/genetics.110.118877
Kullyev, Andrey ; Dempsey, Catherine M. ; Miller, Sarah ; Kuan, Chih Jen ; Hapiak, Vera M. ; Komuniecki, Richard W. ; Griffin, Christine T. ; Sze, Ji Ying. / A genetic survey of fluoxetine action on synaptic transmission in Caenorhabditis elegans. In: Genetics. 2010 ; Vol. 186, No. 3. pp. 929-941.
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