The monoamine neurotransmitter serotonin (5HT) is involved in a variety of brain functions that include mood control, aggression, pain, and cognition, and abnormalities in serotonergic neurotransmission are associated with psychiatric disorders such as depression and migraine headaches. Because many of the molecules involved in neurotransmission and neuronal signaling are highly conserved across evolution, it is possible to use C. elegans to tease out potentially disease-related pathways involving 5HT signaling. We have identified a role for the C. elegans 5HT receptor SER-4 in feedback regulation of 5HT synthesis through regulation of the gene encoding tryptophan hydroxylase (TPH-1), the rate-limiting enzymatic step in 5HT synthesis, using a
tph-1::GFP transgene. Animals lacking
ser-4 show a decreased prevalence of
tph-1::GFP expression in the serotonergic chemosensory ADF neurons. Consistent with this, a C. elegans strains containing a gain of function mutation in a potential effector of 5HTR function, the adenylate cyclase (
acy-1) gene, shows increased
tph-1::GFP expression, and the presence of this
acy-1(gf) mutation can reverse the SER-4-mediated
tph-1::GFP attenuation. This action of adenylate cyclase can be also be mimicked by incubating
ser-4;
tph-1::GFP animals in the presence of forskolin or a water-soluble analog, suggesting that the SER-4 receptor may normally activate this effector pathway. Interestingly, the decreased
tph-1::GFP expression seen in the
ser-4 loss of function mutants is reversed in the presence of cyproheptadine (a 5HT receptor antagonist), a finding indicating that another 5HT receptor(s) actually exerts an inhibitory effect on this cascade.