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doi:10.1534/genetics.104.032540
A more recent version of this article appeared on March 1, 2005.
REGULAR RESEARCH PAPERS |
5HT, fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior
Catherine M Dempsey 1, Scott M Mackenzie 2, Andrew Gargus 2, Gabriela Blanco 2 and Ji Ying Sze 1*
1 University of California Irvine
2 University of California, Irvine
* To whom correspondence should be addressed. E-mail: jsze{at}uci.edu.
Submitted on June 18, 2004
Revised on July 28, 2004
Accepted on 18 November 2004
Drugs that target the serotonergic system are the most commonly prescribed therapeutic agents and are used for the treatment of a wide range of behavioral and neurological disorders. However, the mechanisms of the drug action remain a conjecture. Here, we dissect 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 of stimulated egg laying in C elegans 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 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 independent of synaptic level of 5HT.
Key Words: C. elegans egg-laying behavior, antidepressants, dopamine, egl-30/Gq, serotonin receptors
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