RATIONALE AND OBJECTIVES: The light-enhanced startle paradigm (LES) is suggested to model anxiety, because of the non-specific cue and the long-term effect. In contrast, the fear-potentiated startle (FPS) is suggested to model conditioned fear. However, the pharmacological profiles of these two paradigms are very similar. The present study investigated the effects of putative anxiogenic drugs on LES and FPS and aimed at determining the sensitivity of LES for anxiogenic drugs and to potentially showing a pharmacological differentiation between these two paradigms. METHODS: Male Wistar rats received each dose of the alpha(2)-adrenoceptor antagonist yohimbine (0.25-1.0mg/kg), the 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP, 0.5-2.0mg/kg) or the GABA(A) inverse receptor agonist pentylenetetrazole (PTZ, 3-30mg/kg) and were subsequently tested in either LES or FPS. RESULTS: None of the drugs enhanced LES, whereas mCPP increased percentage FPS and yohimbine increased absolute FPS values. Furthermore, yohimbine increased baseline startle amplitude in the LES, while mCPP suppressed baseline startle in both the LES and FPS and PTZ suppressed baseline startle in the FPS. CONCLUSIONS: In contrast to findings in the FPS paradigm, none of the drugs were able to exacerbate the LES response. Thus, a clear pharmacological differentiation was found between LES and FPS.