EARLY MATERNAL SEPARATION PREDISPOSES ADULT MALE RATS TO COLONIC MUCOSAL BARRIER DYSFUNCTION IN RESPONSE TO AN ACUTE STRESSOR: ROLE OF CORTICOTROPIN-RELEASING HORMONE (CRH)

Mélanie Gareau, Johan D Soderholm, Derrick Yates, Glenda MacQueen¹, Mary H Perdue

Intestinal Disease Research Program and ¹Department of Psychiatry, McMaster University, Hamilton, Ontario

Numerous studies have shown that childhood physical and psychological abuse can lead to affective disorders (ie. depression) in adulthood. Recently, chronic stress and abuse have also been implicated as important contributing factors in the development and course of irritable bowel syndrome (IBS). We established a model of maternal separation (MS) in rats to examine the effects of early psychological trauma on intestinal mucosa function.

AIM: To study whether early trauma induced by MS enhances the reactivity of the colonic mucosa to mild acute stress in adult rats.

METHODS: Sprague-Dawley (SD) rat pups were individually separated from their mother for 3h/day from 4-21 days of age, while control non-handled pups (NH) remained with their dam. On day 22, male rats were identified, weaned and housed individually. Behavioural studies were performed on days 50-70 including sucrose test, novel object test and activity monitoring. Both MS and NH rats were then subjected to mild acute stress (30min of water avoidance) or sham stress on days 80-90. Colonic segments were then collected and mounted in Ussing chambers, while mucosal ion transport (short circuit current, Isc), ion permeability (conductance, G) and macromolecular permeability (horseradish peroxidase flux, HRP) were assessed.

RESULTS: Behavioural tests showed that MS rats were less pleasure-seeking, less exploratory and displayed lower locomotor activity as adults than NH rats. NH rats had low basal levels of Isc, G and HRP flux with mild acute stress inducing a small increase in Isc whereas G and HRP were unaffected. MS rats subjected to sham stress displayed Isc values elevated above baseline, which were further enhanced in the stress group. In MS rats, acute stress caused higher G and a large increase HRP flux with 3-fold increases in comparison to the stressed NH rats. These changes were inhibited by pre-treatment of rats prior to stress with a non-specific CRH antagonist.

CONCLUSION: Early psychological trauma predisposes adult rats to develop mucosal barrier dysfunction in response to a mildly stressful expericence. CRH is an important mediator in stress induced intestinal pathophysiology.

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