Selective Dopamine Transporter Inhibitor CE-123 Modulates Region-Specific Intestinal Mucosal and Immune Responses Following Fear Conditioning and Extinction in Adolescent Female Rats

Background/Objectives: Post-traumatic stress disorder (PTSD) is associated with systemic alterations that may involve the gastrointestinal tract, yet intestinal responses to fear-related learning remain poorly characterized. We investigated intestinal mucosal morphology, MUC2 immunoreactivity, and local immune responses following fear conditioning and extinction, and assessed their modulation by the selective dopamine transporter inhibitor CE-123. Methods: Twenty-four adolescent female Wistar rats were assigned to Control or fear-conditioned (FC) groups receiving Vehicle or CE-123 (10 mg/kg, i.p.) during the extinction phase. Morphometry and immunohistochemical detection of CD68, CD206, iNOS, IL-6, IL-10, and MUC2 were evaluated in the duodenum, jejunum, ileum, and colon. Results: Fear conditioning was associated with marked region-dependent alterations. Among Vehicle-treated animals, villus height was increased in the duodenum and jejunum, accompanied by enhanced immunoreactivity of several inflammation-associated markers. In contrast, the ileum and colon showed distinct profiles characterized mainly by increased IL-6, reduced selected immunoregulatory markers, and decreased MUC2. CE-123 in fear conditioning (FC) showed its clearest attenuation of inflammation-associated responses in the jejunum, where CD68, iNOS, and IL-6 immunoreactivity were reduced. In comparison, this pattern was not consistently observed in other intestinal regions: in the duodenum, only CD68 immunoreactivity was reduced, whereas in the ileum, a reduction was observed only for IL-6. In the colon, both IL-6 and CD68 showed changes in the opposite direction to those observed in the jejunum. Collectively, these region-specific and divergent responses suggest that CE-123 exerts a modulatory rather than uniformly anti-inflammatory effect on intestinal immune responses. CE-123 also produced independent effects in Control animals, including segment-specific changes in mucosal morphometry, MUC2, and selected immune markers, indicating that its actions were not limited to attenuation of conditioning-associated alterations. Conclusions: These findings demonstrate segment-specific intestinal remodeling following fear conditioning and extinction and indicate a context-dependent immunomodulatory effect of CE-123.