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UBC Theses and Dissertations

Sex, serotonin, and adaptive responses to stress Philippe, Tristan Joshua


Few studies have explored the central mechanisms underlying sex differences in stress hypothalamic-pituitary-adrenal axis habituation, defined as a reduction in glucocorticoid steroid hormone responsiveness to non-life-threatening stimuli repeated in a predictable manner. As serotonin (5-hydroxytryptamine; 5-HT) is an important regulator of the HPA axis, the aim of this thesis was to determine how repeated stress-induced declines in HPA axis responsiveness is associated with changes in the 5-HT system. In the first study, males and females showed comparable declines in ACTH and corticosterone responses to repeated restraint, coupled to sex-specific changes in 5-HT 1A receptor mRNA levels in the hippocampus, hypothalamus and in the dorsal raphe nucleus, the latter representing a major source of serotonin in the central nervous system. These findings led me to hypothesize that stress habituation is met by sex differences in 5-HT 1A receptor availability and function. Subsequent studies using a challenge dose of the 5-HT 1A receptor agonist, 8-OH-DPAT, suggested that stress habituation is met by an increase in the sensitivity of postsynaptic 5-HT 1A receptors in both sexes, and by an increase in the sensitivity of presynaptic 5-HT 1A receptors only in males. Considering that stress is often accompanied by 5-HT dependent thermoregulatory responses, I then discovered that restraint-induced hyperthermia declines with repeated exposure, but only in males. Based on these findings to suggest that males and females use different serotonin substrates for adapting to stress, I subsequently characterized the nature by which males and females show differential transcriptional responses in the raphe nucleus, in addition to forebrain regions targeted by the raphe-serotonin system. The results revealed completely different transcriptional profiles between males and females in the raphe nucleus, hypothalamus, and lateral septum. The nature by which these sex-specific alterations contribute or respond to stress habituation remains to be seen. Nonetheless, the current findings continue to underscore how strikingly distinct factors controlling adaptive responses in males and females may be. As stress habituation minimizes the detrimental effects of excessive glucocorticoid exposure, the overall results provide a platform for distinguishing maladaptive from adaptive responses, in addition to understanding sex differences in stress resilience and vulnerability.

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