Serotonin (5HT), fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior.
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.
Dempsey
Catherine M
CM
Department of Anatomy and Neurobiology, College of Medicine, University of California, Irvine, 92697-4040, USA.
Mackenzie
Scott M
SM
Gargus
Andrew
A
Blanco
Gabriela
G
Sze
Ji Ying
JY
D000818:Animals; D001522:Behavior, Animal; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D004298:Dopamine / Q000494:pharmacology*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D017353:Gene Deletion; D015801:Helminth Proteins / Q000187:drug effects / Q000502:physiology; D007099:Imipramine / Q000494:pharmacology*; D010058:Oviposition / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*
D015801:Helminth Proteins; D011985:Receptors, Serotonin; D005473:Fluoxetine; D012701:Serotonin; D007099:Imipramine; D004298:Dopamine