EXCEED THE SPACE PROVIDED. Chemical intolerance (CI) in humans is defined as the inability to tolerate environmental chemicals due to experience of symptoms associated with those chemicals, and these individuals report that prior chemical exposures produced an increased sensitivity to subsequent exposures. To date, there are no clear clinical data that validate whether repeated chemical exposure causes the development of CI in a sensitive subpopulation. Recent work shows that a substantial subset of individuals with CI report a constellation of symptoms that mimic those found in panic disorder and posttraumatic stress disorder (PTSD). Our studies in animals support several investigators' hypotheses that CI may develop as an anxiety disorder akin to panic disorder or an atypical form of PTSD. However, few animal models for CI have been explored. The proposed work emphasizes the parallels between panic disorder/PTSD and CI in the development of a potential animal model for CI. We have recently found that repeated, low-level chemical exposure (formaldehyde [Form] exposure, 0.7-2.4 ppm) produces increased conditioned fear responding to odor previously paired with footshock, with a decreased ability to extinguish this fear response. In addition, repeated Form exposure produced increases in corticosterone levels, and behavioral avoidance patterns that suggest that Form may be acting as a stressor. The proposed work will focus on three behaviors, conditioned freezing behavior, unconditioned anxiety performance and avoidance of odors, and will begin to explore the neural circuitry underlying these changes in behavior after Form exposure. The alms of the proposal are to 1) further characterize the Form-induced changes in conditioned fear, 2) examine the ability of early life stress to predispose animals to increased fear conditioning after daily Form exposure, 3) assess the role of central corticotropin-releasing hormone on Form- induced changes, 4) examine olfactory/limbic brain regions activated during extinction of conditioned fear by measuring c-fos mRNA levels in rats given repeated Form exposure, and 5) examine the effects of pharmacological manipulation of brain sites involved in extinction of conditioned fear. These studies therefore focus on the expression of stress/anxiety/fear responses that may be linked to exaggerated avoidance of chemicals in humans with CI. Exploration of an animal model examining amplification of olfactory/limbic circuitry may guide the development of treatment strategies for CI in humans. PERFORMANCE SITE ========================================Section End===========================================
