In brain catecholaminergic terminals a single decarboxylation step affected by aromatic amino-acid decarboxylase converts phenylalanine to phenylethylamine (PEA) at a rate comparable to that of the central synthesis of dopamine (DA). Subnormal PEA levels have been linked to disorders such as attention deficit and depression, while excess has been invoked particularly in paranoid schizophrenia, in which it is thought to act as an endogenous AMPH and, therefore, would be antagonized by neuroleptics. Though PEA and AMPH show similar effects, both increase extracellular DA concentration, questions still remain in regards to the true function of PEA in the central nervous system. In order to further examine the molecular mechanisms of PEA actions, we have chosen the nematode Caenorhabditis elegans (C. elegans) as our experimental model system. In C. elegans the catecholaminergic neurotransmission includes mostly the dopaminergic system. DA is synthesized in eight sensory neurons (4 CEP, 2 ADE and 2 PDE) and modulates locomotion, learning and egg laying activity. All the known dopaminergic components involved in DA synthesis, vesicle storage, release and reuptake are highly conserved between the worm and mammals. Previously, we showed that AMPH induces a complete lack of motor function in nematodes placed in water. We named this behavior swimming-induced paralysis (SWIP). Evidences suggested that AMPH-induced SWIP behavior is mediated by DA efflux through the dopamine transporter (DAT-1). This causes an excess of extracellular DA concentrations which over-stimulate the DA receptors and ultimately generates SWIP. Here we show that, although PEA and AMPH have very similar molecular structures, PEA is more potent than AMPH in generating SWIP behavior. Our data show that PEA significantly induces SWIP behavior in wild-type animals at a stronger rate when compared to AMPH. To further examine the mode of action of PEA-induced SWIP, we treated DAT-1, DOP-2 and DOP-3 receptor knockout animals (
dat-1,
dop-2 and
dop-3) with different concentration of PEA.
dat-1 and
dop-3 animals displayed less susceptibility to PEA-induced SWIP than wild-type animals suggesting that these two proteins partially mediated PEA-induced phenotype. On the contrary, in
dop-2 animals, PEA-induced SWIP occurred at levels similar to wild-type animals. Ongoing biochemistry and amperometric studies will establish the molecular mechanism underling PEA effects in cultured neurons isolated from C. elegans embryos. Importantly, these findings demonstrate the utility of the nematode model for the dissection of molecular determinants of PEA-modulated behavior.