Activation of the neurotrophin receptor Trk induces the release of neurotrophins. However, little is known about the ability of released neurotrophins to modulate their own synthesis in an autocrine manner. As a step towards understanding the role of Trk in regulating the synthesis of neurotrophins, we exposed NIH-3T3 cells expressing TrkA or TrkC receptors to their cognate ligands as well as to GM1, a ganglioside that activates TrkA and TrkC by inducing the release of neurotrophin-3. Nerve growth factor and neurotrophin-3 synthesis were then determined by measuring the relative levels of protein and mRNA. TrkA-expressing cells exposed to human recombinant nerve growth factor exhibited higher levels of nerve growth factor mRNA. Human recombinant neurotrophin-3 evoked an increase in nerve growth factor mRNA in both TrkA and TrkC-expressing cells. GM1 elicited a time-dependent increase in nerve growth factor protein and mRNA in NIH-3T3 cells expressing TrkA or TrkC receptor but not in wild-type cells. Surprisingly, GM1 failed to change neurotrophin-3 levels. The ability of GM1 to increase nerve growth factor mRNA levels was blocked by TrkC-IgG but not by TrkB-IgG receptor body. These data suggest that released neurotrophin-3 may activate a positive autocrine loop of nerve growth factor synthesis by Trk activation.