Behavioral sensitization after repeated formaldehyde exposure in rats

Toxicol Ind Health. Apr-Jun 1999;15(3-4):346-55. doi: 10.1177/074823379901500309.


Multiple chemical sensitivity (MCS) is a phenomenon whereby individuals report increased sensitivity to chemicals in the environment, and attribute their sensitivities to prior exposure to the same or often structurally unrelated chemicals. A leading hypothesis suggests that MCS is akin to behavioral sensitization observed in rodents after repeated exposure to drugs of abuse or environmental stressors. Sensitization occurring within limbic circuitry of the central nervous system (CNS) may explain the multisymptom complaints in individuals with MCS. The present studies represent the continuing development of an animal model for MCS, the basis of which is the CNS sensitization hypothesis. Three behaviors were assessed in rats repeatedly exposed to formaldehyde (Form) inhalation. In the first series of experiments, rats were given high-dose Form exposure (11 parts per million [ppm]; 1 h/day x 7 days) or low-dose Form exposure (1 ppm; either 1 h/day x 7 days or 1 h/day x 5 days/week x 4 weeks). Within a few days after discontinuing daily Form, cocaine-induced locomotor activity was elevated after high-dose Form or 20 days of low-dose Form inhalation. Approximately 1 month later, cocaine-induced locomotor activity remained significantly elevated in the 20-day Form-exposed rats. The second experiment assessed whether prior exposure to Form (20 days, as above) would alter the ability to condition to an odor (orange oil) paired with footshock. The results suggested a tendency to increase the conditioned fear response to the odor but not the context of the footshock box, and a decreased tendency to extinguish the conditioned fear response to odor. The third experiment examined whether CNS sensitization to daily cocaine or stress would alter subsequent avoidance responding to odor (Form). Daily cocaine significantly elevated approach responses to Form, while daily stress pretreatment produced a trend in the opposite direction, producing greater avoidance of Form. Preliminary studies indicated that repeated daily Form inhalation (20 days, as above) produced a greater avoidance to subsequent Form presentation, suggesting that daily Form inhalation may serve as a stressor. The results support the hypothesis that repeated chemical exposure in rats may produce CNS plasticity manifest as greater sensitivity to dopaminergic drugs, enhanced fear conditioning to odor paired with an aversive event, and greater avoidance of odors. Some of these behavioral changes observed in rats may provide a link with symptoms in a subset of individuals with MCS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Avoidance Learning / drug effects
  • Behavior, Animal / drug effects*
  • Central Nervous System / drug effects*
  • Cocaine / pharmacology*
  • Cross Reactions
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Fear / drug effects
  • Female
  • Formaldehyde / toxicity*
  • Male
  • Models, Biological
  • Motor Activity / drug effects*
  • Multiple Chemical Sensitivity*
  • Odorants
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors


  • Formaldehyde
  • Cocaine