Repeated low level formaldehyde exposure produces enhanced fear conditioning to odor in male, but not female, rats.

Multiple chemical sensitivity (MCS) is an ill-defined disorder in humans attributed to exposure to volatile organic compounds. This study draws on apparent parallels between individuals with posttraumatic stress disorder (PTSD) and panic disorder and a subset of those reporting MCS, using a conditioned fear task in rats. Male and female Sprague-Dawley rats were given repeated exposure to 2 ppm formaldehyde (Form) (1 h/day x 5 days/week x 4 week) or air, and after 2-3 weeks, rats were trained on the conditioned fear task. One half of Air and Form rats were given odor (orange oil, the conditioned stimulus, CS) paired with footshock (PRD) and the other half was given the same stimuli in an unpaired manner (UNP). After 24 h, rats were placed into the same context without the CS or footshock. Male and female PRD groups demonstrated contextual freezing 5-15% of the time, while the UNP groups showed freezing 30-50% of the time, with no effect of Air or Form pretreatment. For the next 5 days, rats were placed into a novel context and tested for freezing in the absence or presence of the CS. In male rats, Form pretreatment produced a significantly greater freezing response in both UNP and PRD groups in the presence of the CS, with no differences in freezing in the absence of the CS. In female rats, no significant differences between Form pretreated rats and Air controls were observed in either the PRD or UNP groups. The increase in conditioned fear responding to the CS after Form exposure in males suggests that repeated low-level Form may act as a stressor to produce sensitized responding within olfactory/limbic pathways, and may help explain the panic-like responses observed in a subset of individuals reporting MCS. Furthermore, the male/female differences suggest a gonadal hormonal contribution to this behavior.