Neuroanatomical and neurochemical mechanisms involved in conditioned fear and anxiety will be investigated in rats and in humans using the acoustic startle reflex. In both rats and humans, startle amplitude can be increased by eliciting the reflex in the presence of a cue previously paired with a shock (fear-potentiated startle equal explicit cue conditioning) as well as exposure to the experimental situation where fear conditioning occurred (context conditioning). In rats, lesions of the amygdala block both explicit cue conditioning and context conditioning, whereas lesions of the bed nucleus of the stria terminalis (BNST), which also projects to the startle pathway, block context conditioning but not explicit cue conditioning. Hence, the Bnst may be especially important for context conditioning because it receives a heavy inputs from the hippocampus. The test this, effects of chemical lesions of either the lateral and basolateral amygdala, the dorsal vs. Ventral hippocampus of the bed nucleus of the stria terminalis will be given either before or after training to asses the possible differential effects of these lesions on both the acquisition and expression of explicit cue and contextual fear conditioning. Patients with post-traumatic stress syndrome (PTSD) seem to display abnormal context conditioning buy normal explicit cue conditioning. Because PTSD has been associated with a dysregulation of brain norepinephrine (NE), and central beta- adrenergic receptors are important for modulation of aversive memories, we hypothesize that context conditioning will be more sensitive than explicit cue conditioning to manipulations of central NE. In rats and healthy humans the effects of the drugs propranolol, yohimbine, or buspirone given systemically will be tested on both context and explicit cue conditioning. We hypothesize that propranolol will be more effective in blocking the acquisition of context conditioning than explicit cue conditioning, that yohimbine will be more effective in facilitating the acquisition of context conditioning than explicit cue conditioning, and that buspirone will block the expression of explicit cue conditioning but not the expression of contextual fear conditioning. In PTSD patients and age-matched healthy controls the effects of propranolol will be evaluated on context conditioning vs. Explicit cue conditioning. Similar predictions are made for these patients excepts that the magnitude of context conditioning is expected to be greater in PTSD vs age-matched controls and this difference in startle magnitude may be normalized by propranolol.
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