Increased susceptibility to transcriptional changes with novel stressor in adrenal medulla of rats exposed to prolonged cold stress

The response to stress is influenced by prior experience with the same or different stressor. For example, exposure of cold pre-stressed rats to heterotypic (novel) stressors, such as immobilization (IMO), triggers an exaggerated release of catecholamines and increase in gene expression for adrenomedullary tyrosine hydroxylase (TH), the rate limiting catecholamine biosynthetic enzyme. To study the mechanism, we examined induction or phosphorylation of several transcription factors, which are implicated in IMO-triggered regulation of TH transcription, in rats exposed to cold (4 °C) for up to 28 days and then subjected to IMO. Levels of c-fos increased transiently after 2-6 h and returned to basal levels after 1-28 days cold stress. Fra-2, was unaffected by short term cold, but was induced about 2-fold by 28 days continual cold. In contrast, there were no significant changes in CREB phosphorylation or Egr1 induction. Rats, with and without pre-exposure to 28 days cold, were subjected to single IMO for up to 2 h. Phosphorylation of CREB after 30 min IMO was greater in cold pre-exposed rats. Induction of Egr1 was three times higher in cold pre-exposed rats and remained significantly elevated even 3 h after cessation of IMO. Exposure to IMO triggered a 10-20-fold elevation in Fra-2 in both groups, which was even higher 3 h after the IMO. However, Fra-2 was more heavily phosphorylated following IMO stress in cold pre-exposed animals. The results reveal that sensitization to novel stress in cold pre-exposed animals is manifested by exaggerated response of several transcription factors.