Pharmacological analysis of fear-potentiated startle

1. The potentiated startle paradigm measures conditioned fear by an increase in the amplitude of a simple reflex (the acoustic startle reflex) in the presence of a cue previously paired with shock. This paradigm offers a number of advantages as an alternative to most animal tests of fear or anxiety because it involves no operant and is reflected by an enhancement rather than a suppression of ongoing behavior. 2. A variety of drugs which block anxiety in people block fear-potentiated startle in rats. Although the 5-HT1A agonist buspirone is especially effective in blocking fear-potentiated startle, more selective 5-HT1A agonists have been less consistently effective. However, when these drugs are combined with only partially effective doses of the D1 antagonist, SCH23390, a full blockade of fear-potentiated startle is achieved. Hence, synergistic actions appear to occur between serotonin and dopamine in modulating the expression of fear-potentiated startle. 3. In addition to pharmacological studies, physiological studies are being used to define the neural pathways necessary for a visual conditioned stimulus to alter the acoustic startle reflex. The current working hypothesis is that the conditioned stimulus activates the central nucleus of the amygdala through a pathway involving the lateral geniculate nucleus, perirhinal cortex, and lateral and basolateral amygdaloid nuclei. The central nucleus of the amygdala then projects directly to the acoustic startle pathway so as to modulate the startle response. Chemical or electrolytic lesions of either the central nucleus or the lateral and basolateral nuclei of the amygdala block the expression of fear-potentiated startle. These latter amygdaloid nuclei may actually be the site of plasticity for fear conditioning, because local infusion of the NMDA antagonist AP5 blocks the acquisition but not the expression of fear-potentiated startle. 4. Finally, we have begun to investigate brain systems that might be involved in the inhibition of fear. Local infusion of AP5 into the amygdala was found to block the acquisition of experimental extinction, a prototypical method for reducing fear. We have also established a reliable procedure for producing conditioned inhibition of fear-potentiated startle and hope to eventually understand the neural systems involved in this phenomenon.