Teneurin C-terminal associated peptide-1 attenuates chronic stress in male rats

Hyperactivity of the hypothalamic–pituitary–adrenal axis core stress response system can lead to anxiety, chronic stress, and other neuropsychiatric disorders, such as major depressive disorder and posttraumatic stress disorder. Mitigating this response requires novel interventions to overcome the delayed efficacy and nonspecificity that characterize the currently available, suboptimal chronic stress treatments. Teneurin C-terminal Associated Peptide (TCAP)-1, a naturally occurring neuropeptide, is an established regulator of corticotropin-releasing factor (CRF) mediated stress responses. Although prior work has characterized the ability of TCAP-1 to attenuate the physiological and behavioral expression of stress in acute stress models, the effect of TCAP-1 on chronic stress remains unexplored. Using a chronic unpredictable stress model, the impact of TCAP-1 on the expression of chronic stress in male rats was investigated. Administration of TCAP-1 attenuated plasma corticosterone levels by 56.4% and increased open field center time by 282.04%, reflecting improvements in the physiological and behavioral manifestations of chronic stress, respectively. In contrast, a nonpeptide CRF ₁ receptor antagonist, CP-154,526, demonstrated no effect on the chronic stress-induced physiological and behavioral profile. These results provide evidence for the neuromodulatory role of TCAP-1 in the chronic stress response, supporting its potential as a clinically relevant anxiolytic. The divergence between TCAP-1 and CP-154,526 in this chronic model is consistent with the broader clinical failure of CRF ₁ receptor antagonists in phase 2 human trials and highlights the potential translational advantage of TCAP-1’s distinct, upstream mechanism of action.