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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Fluoxetine is one of the most commonly prescribed medications for many behavioral and neurological disorders. Fluoxetine acts primarily as an inhibitor of the serotonin reuptake transporter (SERT) to block the removal of serotonin from the synaptic cleft, thereby enhancing serotonin signals. While the effects of fluoxetine on behavior are firmly established, debate is ongoing whether inhibition of serotonin reuptake is a sufficient explanation for its therapeutic action. Here, we provide evidence of two additional aspects of fluoxetine action through genetic analyses in Caenorhabditis elegans. We show that fluoxetine treatment and null mutation in the sole SERT gene mod-5 eliminate serotonin in specific neurons. These neurons do not synthesize serotonin but import extracellular serotonin via MOD-5/SERT. Furthermore, we show that fluoxetine acts independently of MOD-5/SERT to regulate discrete properties of acetylcholine (Ach), gamma-aminobutyric acid (GABA), and glutamate neurotransmission in the locomotory circuit. We identified that two G-protein-coupled 5-HT receptors, SER-7 and SER-5, antagonistically regulate the effects of fluoxetine and that fluoxetine binds to SER-7. Epistatic analyses suggest that SER-7 and SER-5 act upstream of AMPA receptor GLR-1 signaling. Our work provides genetic evidence that fluoxetine may influence neuronal functions and behavior by directly targeting serotonin receptors.

Objectives: To evaluate (1) the appropriateness of the after-hours referral (AHR), (2) clinical characteristics of urgently referred patients, and (3) parental compliance with disposition recommendations by the After-Hours Call Center of the Children's Hospital, Denver, Colo. Subjects:Patients of Denver, Colo, pediatricians who called after office hours were triaged by nurses using a computerized triage system, and were referred for afterhours evaluation to 1 of 5 urgent care sites (N = 409).Design: Data were collected at each site for 2-week periods every 3 months, from October 1996 to October 1997 (total study period, 10 weeks). Appropriateness of AHRs (diagnoses, clinical interventions, and final dispositions) were determined by a questionnaire that was completed by the evaluating physician. Parental compliance with the AHR was assessed by review of the after-hours site patient database and by telephone survey. Results:Of the referred patients, 339 (82.9%) complied with the recommendation for AHR and, of these, physician questionnaires were completed for 332 (97.9%). The mean percentage of evaluated patients judged appropriate was 90.7% and did not differ statistically by site or by physician training. A history indicating a potentially serious condition was the most common reason for judging a referral appropriate (80.1%), followed by patient discomfort (53.3%), findings from a physical examination (42.5%), parental anxiety (41.5%), and an urgent need for diagnostic test or therapy (34.7%). Of evaluated patients, 37.0% had a diagnostic test, and in 43.5% of cases, the evaluating physician thought a therapeutic intervention was necessary that night. Of the total sample, 93.4% were discharged and 6.6% were admitted to the hospital. The major reasons given by families for noncompliance were lack of understanding of the disposition recommendation and disagreement with the need for urgent referral.Conclusions: Approximately 90% of patients who complied with a referral for urgent evaluation by the AfterHours Call Center were judged by the evaluating physician to have been appropriately referred. The appropriateness rate for all referrals may be lower if there is significant self-selection in those families who do not comply.