Antagonists at the serotonin-3 receptor can reduce the fear-potentiated startle response in the rat: evidence for different types of anxiolytic activity?

The current study evaluated three serotonin-3 (5-HT3) antagonists for potential anxiolytic effects in rats by using the fear-potentiated startle paradigm. Because initial studies did not show an effect of the 5-HT3 antagonists, the authors explored the question of whether altering the training conditions under which the conditioned fear is formed would alter the sensitivity of the paradigm to the effects of the 5-HT3 antagonists. Two fear-conditioning protocols were used: 1) 10 conditioning trials on each of 2 days using 0.5 mA of foot shock and 2) 15 conditioning trials in 1 day using 0.25 mA of foot shock. Ondansetron (0.001-1.0 mg/kg), (R)-zacopride (0.0001-1.0 mg/kg), granisetron (0.001-1.0 mg/kg), diazepam (0.32-3.2 mg/kg) and buspirone (0.56-5.6 mg/kg) were evaluated for their ability to reduce the potentiated startle produced by both conditioning protocols. Although diazepam and buspirone effectively reduced the potentiated startle produced by both protocols, the 5-HT3 antagonists were potently effective only in the second protocol. Subsequent experiments demonstrated that the 5-HT3 antagonists block startle potentiation only when the lower (i.e., 0.25 mA) shock intensity is used during training. These results suggest the possibility that different conditioning protocols may produce qualitatively different anxiety states, which can be differentiated by the 5-HT3 antagonists, but not by diazepam or buspirone.