Panic Disorder affects roughly 1-2% of the general population with more women than men affected. Although drug and behavioral treatments are relatively effective in treating this disorder, its etiology and pathophysiology remain poorly understood. Pharmacological challenges and treatment in humans have helped define panic disorder, but ethical and practical constraints limit scientific exploration. We propose further neurochemical and behavioral investigation of the provocation of anxiety symptoms in nonhuman primates which reliably mirror significant aspects of human panic response. We have labeled these symptoms, """"""""Acute Endogenous Distress"""""""" (AED). The proposed work will examine the hypothesized central role of the locus ceruleus in mediating these acute anxiety responses and the possible role of dysregulation of several neurochemical systems in modulating LC responsivity. These experiments will employ agents capable of provoking panic in patients which we have previously demonstrated as effective in primates, particularly sodium lactate and yohimbine. Our goals include determination of the role of centrally administered CRF, the effects of serotonin and its depletion, and the possible role of Glutamate in the pathophysiology of AED. Comparisons of pre- and post-treatment CSF levels of major neurotransmitters and cardiac responsivity during AED provocation will permit assessment of baseline and altered neurochemical status on AED susceptibility. In addition to the pharmacological probes, our primate studies will allow us to examine developmentally the hypothesized role of early attachment/mastery experience in the emergence of AED and its neurochemical underpinnings. The effects of recent stressful events, which have been linked theoretically to panic vulnerability in humans, will also be studied. Systematic observations of a range of previously defined anxiety patterns form the core of the AED assessments, while the possible cognitive effects of AED will employ novel computer-based video tasks of varying difficulty. The use of primates in the systematic examination of hypotheses which have emerged from the human literature, but which remain untestable at the human level, is critical to our understanding and ultimate treatment of panic disorder.
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