Chemical Intolerance (CI) in humans is defined as the inability to tolerate environmental chemicals due to experience of symptoms associated with those chemicals. Although CI is prevalent in individuals claiming that prior chemical exposures produced their intolerance, the underlying etiology remains unknown. A high percentage of individuals reporting CI present with psychiatric symptomatology, and some investigators have suggested that CI is an atypical form of posttraumatic stress disorder (PTSD). The proposed work emphasizes the parallels between PTSD and CI in the development of a potential animal model for CI. Animal models of four phenomena appear most suitable for examining PTSD and, therefore, CI: 1) sensitization of the central nervous system (CNS), 2) conditioned fear, 3) extinction of a conditioned fear response and 4) avoidance of a conditioned stimulus. In support of CI as a PTSD-like phenomenon, recent studies in this laboratory have found that rats given repeated daily inhalation of low levels of formaldehyde (Form) demonstrated long-term cross-sensitization to cocaine-induced locomotion. In addition, daily Form treated rats exhibited increased avoidance to subsequent Form, and a reduced ability to extinguish a conditioned fear response to an odor paired with foot shock. Since Form does not penetrate beyond the upper airway, it is likely that Form serves as a stressor to produce sensitization. For the proposed studies, four exposure doses of Form will be employed. The first specific aim will test the hypothesis that repeated Form exposure produces increases in stress/anxiety responses after subsequent Form presentation in the same or different environment from which original exposures occurred. Serum corticosterone levels and behaviors reflective of anxiety/stress will be monitored during and after re-exposure to Form. The second specific aim will examine the hypothesis that repeated Form induces sensitization to later Form presentation and cross-sensitization to cocaine via the hypothalamic-pituitary-adrenal (HPA) axis. Cross-sensitivity to cocaine will be monitored behaviorally, and nucleus accumbens dopamine levels will be measured by in vivo microdialysis. Form sensitization to itself will be measured by assessment of nucleus accumbens dopamine levels and also behaviorally by monitoring avoidance responses to later Form presentation.
This aim will also perform adrenalectomy in one-half of rats to determine whether an intact HPA axis is required for Form-induced effects. The third specific aim will test the hypothesis that repeated Form exposure produces a decreased ability to extinguish a conditioned fear response. The specificity of the effect (context vs odor or tone) will also be explored. The study of behavioral and neurochemical sensitization, conditioned fear and extinction in Form-exposed rodents will provide a mechanistically-based animal model system for studying the development and maintenance of CI in humans.
