Serotonin regulates vertebrate and invertebrate behaviors such as feeding, mood, aggression, perception, reproduction, and sleep. Serotonin has been implicated in psychiatric disorders such as depression, and selective serotonin reuptake inhibitors (SSRI), such as fluoxetine (aka Prozac), inhibit the Serotonin Reuptake Transporter (SERT) and potentiates serotonin signaling to improve moods. However, while SSRIs block SERT activity immediately, behavioral changes may take weeks to develop, raising questions on how serotonin signaling contributes to psychiatric disorders and how long-term restoration of serotonin signaling alleviates symptoms.
We are addressing how SSRIs like fluoxetine regulate behavior using the C. elegans egg-laying circuit as a model system. Egg laying is promoted by serotonin which is released by a pair of command neurons (HSNs) that innervate and regulate the contractility of the vulval muscles. Low levels of fluoxetine promote egg laying, but high levels of fluoxetine can inhibit it. This suggests that small increases in serotonin activate excitatory postsynaptic serotonergic receptors to stimulate vulval muscle contractility, while saturation of serotonin can inhibit behavior. Using behavior assays and Ca2+ imaging, we observed from our model that high concentrations of fluoxetine can inhibit HSN activity and egg laying due to increases in serotonin. We predict that inhibition of egg laying by fluoxetine requires inhibitory serotonin receptors MOD-1 and SER-4, thus mutant animals lacking these receptors will be more active. Together, these results would support a model where continuous treatment with fluoxetine ultimately decreases serotonin release and signaling by inhibiting activity of serotonin releasing neurons.
