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,
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