Serotonin (5-HT) levels in the hemolymph of crustaceans has been implied to alter aggressiveness which influences social interactions. The activation of IP3 as a second messenger cascade within crayfish motor neurons in response to application of 5-HT, suggests that the 5-HT receptor subtypes on the motor neurons are analogous to the vertebrate 5-HT2A receptors. Based on evidence in other systems, it would be expected that chronically sustained 5-HT levels in aggressive individuals would result in a compensatory negative feed-back regulation and/or that target tissues would diminish their sensitivity to high levels of circulating, free 5-HT. We addressed the issue of up- and down-regulation in the sensitivity of the responsiveness to exogenously applied 5-HT at the NMJs of crayfish in which the animals have altered endogenous 5-HT levels. Injections of the 5-HT1 and 5-HT2 vertebrate receptor agonist, 1-(3-Chlorophenyl) piperazine dihydrochloride (m-CPP), for 1 week resulted in a decreased responsiveness to application of 5-HT. The compound p-chlorophenylalanine (p-CPA) blocks the enzymatic synthesis of 5-HT and following 7 days of p-CPA injections, a super-sensitivity to exogenous application of 5-HT for both tonic and phasic neuromuscular junctions (NMJs) was observed. However, acute applications of p-CPA and m-CPP, followed by extensive saline washing, did not reveal any altered receptivity to 5-HT application.