Serotonin (5HT), Fluoxetine, Imipramine and Dopamine Target Distinct 5HT Receptor Signaling to Modulate Caenorhabditis elegans Egg-Laying Behavior

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.T HE selective serotonin reuptake inhibitor (SSRI) transmission (Di Matteo et al. 2001). On the other fluoxetine and the tricyclic antidepressant imiprahand, antagonists to the ionotropic receptor 5HT3 inmine represent two major classes of therapeutics used hibit dopamine function in the rat mesocorticolimbic for treatment of a wide range of behavioral and neurosystem (Gillies et al. 1996). Therefore, the action of logical disorders from depression to autism and schizoantidepressants at specific 5HT receptor subtypes could phrenia. The classically recognized action of these drugs underlie the unique spectrum of the therapeutic effiis to block uptake of serotonin (5HT) by the membrane cacy of the drugs. However, distinction between the 5HT transporter (SERT), which results in an increase action of a drug on SERT and on 5HT receptors in vivo in synaptic 5HT availability (Baldessarini 1996). In is difficult, and the role of 5HT receptor subtypes in addition, it has been shown in vitro that these drugs,

Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs

“…The hypothesis that the Asm/ceramide system plays a role in the effect of antidepressants was confirmed by the abrogation of the previously-described effect of fluoxetine on egg laying 17,18 , which was abrogated in ams-1-deficient C. elegans (Fig. 2e).…”

A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans

“…In nearly all tested paradigms, fluoxetine and imipramine induce behavioral changes similarly to exogenous 5-HT Nurrish et al 1999), implying that fluoxetine regulates 5-HT inputs to these neural circuits. However, the tryptophan hydroxylase gene tph-1 is required for 5-HT biosynthesis in C. elegans (Sze et al 2000), mod-5 encodes its sole SERT (Ranganathan et al 2001), and yet fluoxetine could stimulate egg laying and inhibit locomotion in mod-5 and tph-1 mutants Choy and Thomas 1999;Ranganathan et al 2001;Dempsey et al 2005). These findings provided a basis for further investigation into genes and synaptic functions regulated by 5-HT and the impact of fluoxetine on 5-HT signaling.…”

“…Second, a variety of studies with cultured mammalian cells and mouse brain slices showed that SSRIs and tricyclic antidepressant agents (TCAs) have high affinities to many 5-HT receptor subtypes and act as agonists or antagonists depending on particular receptors being tested (Ni and Miledi 1997;Kroeze and Roth 1998;Eisensamer et al 2003). Third, genetic analyses of the nematode Caenorhabditis elegans in our laboratory and others showed that fluoxetine and the TCA imipramine (Tofrani) could influence behavior independent of SERT function Ranganathan et al 2001;Dempsey et al 2005). In this study, we carried out a systematic survey of SSRIs treatment in C. elegans to gain new insights into actions of SSRIs on the 5-HT system and other neurotransmitter systems.…”

SER-7, aCaenorhabditis elegans5-HT7-like Receptor, Is Essential for the 5-HT Stimulation of Pharyngeal Pumping and Egg Laying

“…Multiple 5-HT receptors are involved in the regulation of egg laying. Vulval muscle appears to express a Ga q -coupled 5-HT receptor (SER-1) that is coupled to the entry of external Ca 21 through EGL-19, an L-type Ca 21 channel (Shyn et al 2003;Dempsey et al 2005). 5-HT switches the muscle from an inactive to an active state capable of contraction 1 (Waggoner et al 1998).…”