Serotonin (5HT), Fluoxetine, Imipramine and Dopamine Target Distinct 5HT Receptor Signaling to Modulate Caenorhabditis elegans Egg-Laying Behavior
- 1 March 2005
- journal article
- Published by Oxford University Press (OUP) in Genetics
- Vol. 169 (3) , 1425-1436
- https://doi.org/10.1534/genetics.104.032540
Abstract
Drugs that target the serotonergic system are the most commonly prescribed therapeutic agents and are used for treatment of a wide range of behavioral and neurological disorders. However, the mechanism of the drug action remain a conjecture. Here, we dissect the genetic targets of serotonin (5HT), the selective 5HT reuptake inhibitor (SSRI) fluoxetine (Prozac), the tricyclic antidepressant imipramine, and dopamine. Using the well-established serotonergic response in C. elegans egg-laying behavior as a paradigm, we show that action of fluoxetine and imipramine at the 5HT reuptake transporter (SERT) and at 5HT receptors are separable mechanisms. Even mutants completely lacking 5HT or SERT can partially respond to fluoxetine and imipramine. Furthermore, distinct mechanisms for each drug can be recognized to mediate these responses. Deletion of SER-1, a 5HT1 receptor, abolishes the response to 5HT but has only a minor effect on the response to imipramine and no effect on the response to fluoxetine. In contrast, deletion of SER-4, a 5HT2 receptor, confers significant resistance to imipramine while leaving the responses to 5HT or fluoxetine intact. Further, fluoxetine can stimulate egg laying via the Gq protein EGL-30, independent of SER-1, SER-4, or 5HT. We also show that dopamine antagonizes the 5HT action via the 5HT-gated ion channel MOD-1 signaling, suggesting that this channel activity couples 5HT and dopamine signaling. These results suggest that the actions of these drugs at specific receptor subtypes could determine their therapeutic efficacy. SSRIs and tricyclic antidepressants may regulate 5HT outputs independently of synaptic levels of 5HT.Keywords
This publication has 55 references indexed in Scilit:
- C. elegans: des neurones et des gènesmédecine/sciences, 2003
- Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutantNature, 2000
- Facilitation of Synaptic Transmission by EGL-30 Gqα and EGL-8 PLCβ: DAG Binding to UNC-13 Is Required to Stimulate Acetylcholine ReleasePublished by Elsevier ,1999
- Serotonin Inhibition of Synaptic TransmissionNeuron, 1999
- Characterization of a Novel Serotonin Receptor from Caenorhabditis elegansJournal of Neurochemistry, 1999
- Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)1A receptors: WAY 100,635-reversible actions of the highly selective ligands, flesinoxan and S 15535Synapse, 1998
- A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegansNature, 1995
- Localization of FMRF amide‐like peptides in Caenorhabditis elegansJournal of Comparative Neurology, 1992
- The structure of the nervous system of the nematodeCaenorhabditis elegansPhilosophical Transactions of the Royal Society of London. B, Biological Sciences, 1986
- Serotonin and Octopamine in the Nematode Caenorhabditis elegansScience, 1982