ANATOMY AND PHARMACOLOGY OF FEAR-POTENTIATED STARTLE

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Neuroanatomical and neurochemical mechanisms involved in associative learning, using the acoustic startle reflex in rats, will be investigated. Acoustic startle is a short latency reflex mediated by a simple neural pathway. Startle amplitude can be increased by eliciting the reflex in the presence of a light previously paired with a shock (fear-enhanced or fear-potentiated startle). This effect can be blocked by drugs which reduce anxiety clinically, by lesions of the central nucleus of the amygdala or lesions that prevent visual information from reaching the amygdala. Low level electrical stimulation of the amygdala markedly increases acoustic startle amplitude via a direct projection from the amygdala to the acoustic startle circuit. Thus, fear-potentiated startle represents a model of fear or anxiety in animals where much of the neural circuitry has been delineated. Hence, it is now possible to begin to determine the cellular mechanisms involved in both the acquisition and expression of associative fear conditioning. The role of excitatory amino acid receptors in acquisition, expression and extinction of fear-potentiated startle will be analyzed by locally infusing N-methyl-D-aspartate (NMDA) vs. nonNMDA receptor antagonists into different amygdala nuclei before fear-potentiated startle training,testing or extinction sessions using a visual conditioned. Possible roles of protein kinase inhibitors will also be evaluated. Other studies will test if NMDA antagonists win block acquisition when given immediately after training. Other studies will evaluate whether NMDA antagonists will affect acquisition vs. expression of potentiated startle using either an auditory conditioned stimulus or contextual cues. Other studies win test effects of local administration of drugs into the acoustic startle pathway to begin to test cellular hypotheses about how activation of the amygdala can increase startle via its direct projection to the startle circuit. The results will have implications for understanding the neural basis of learning and memory, as well as potential development of more specific anxiolytic drugs.