Mutations in the Caenorhabditis elegans serotonin reuptake transporter MOD-5 reveal serotonin-dependent and -independent activities of fluoxetine

We isolated two mutants defective in the uptake of exogenous serotonin (5-H T) into the neurosecretory motor neurons of Caenorhabditis elegans. These m utants were hypersensitive to exogenous 5-HT and hyper-responsive in the ex perience-dependent enhanced slowing response to food modulated by 5-HT. The two allelic mutations defined the gene mod-5 (modulation of locomotion def ective), which encodes the only serotonin reuptake transporter (SERT) in C. elegans. The selective serotonin reuptake inhibitor fluoxetine (Prozac) po tentiated the enhanced slowing response, and this potentiation required mod -5 function, establishing a 5-HT- and SERT-dependent behavioral effect of f luoxetine in C. elegans. By contrast, other responses of C. elegans to fluo xetine were independent of MOD-5 SERT and 5-HT. Further analysis of the MOD -5-independent behavioral effects of fluoxetine could lead to the identific ation of novel targets of fluoxetine and could facilitate the development o f more specific human pharmaceuticals.