¹Fujita Health University, Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Aichi, Japan, ²Fujita Health University, International Center for Brain Science (ICBS), Aichi, Japan, ³Fujita Health University, Department of Advanced Diagnostic System Development, Aichi, Japan, ⁴Fujita Health University, Laboratory of Health and Medical Science Innovation (HMSI), Aichi, Japan, ⁵Fujita Health University, Japanese Drug Organization of Appropriate Use and Research, Aichi, Japan

Background: Major depressive disorder (MDD) is a significant cause of social and economic burdens, and suicide (RC Kessler., Psychiatr Clin North Am., 2012). Although the monoamine hypothesis has dominated on the pathophysiology and pharmacotherapy of MDD, approximately 40% of patients do not respond to current pharmacotherapies (Y Dwivedi et al., Dialogues Clin Neurosci., 2014). Thus, the development of antidepressants based on novel pathophysiological mechanisms of MDD is required. The metabolites in tryptophan–kynurenine (TRP–KYN) pathway influence neural activity. Dysregulation of this pathway is associated with the pathophysiology of neuropsychiatric disorders, including MDD (H Fujigaki et al., Neuropharmacology., 2017). Increased levels of kynurenic acid (KYNA) antagonize the α7 nicotinic acetylcholine receptor (α7nAChR), which may be associated with depression-like behaviors (Mori et al., Behav Brain Res., 2021). However, it remains unclear that how chronic stress exposure, a principal etiological factor in MDD, influences TRP–KYN pathway and causes stress-induced behavioral changes.

Aims & Objectives: To identify a novel therapeutic molecular target on MDD, we investigated whether the TRP-KYN pathway is associated with stress-induced behavioral changes.

Method: Mice were exposed to chronic unpredictable mild stress (CUMS) for 4 weeks and subjected to behavioral tests (locomotor activity , open field , social interaction , and tail suspension tests). Levels of TRP-KYN metabolites and the expression of their enzymes were measured in the hippocampus. KMO (kynurenine 3-monooxygenase) heterozygous (+/−) mice were used to investigate stress vulnerability. The effect of nicotine (s.c.) on CUMS-induced １）behavioral changes, 2）an increased levels of serum corticosterone (CORT), and 3）changes in molecules involved in the hypothalamic–pituitary–adrenal (HPA) axis were evaluated. Finally, we investigated whether nAChR plays a pivotal role in the antidepressant effects induce by nicotine using methyllycaconitine (MLA; α7nACh antagonist) and the dihydro-β-erythroidine hydrobromide (DHβE; α4β2nAChR antagonist).

Results: CUMS decreased social interaction time, but increased immobility time in tail suspension that associated with increased levels of serum CORT. Further, CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. KMO(+/−) mice exhibited the increased KYNA levels and were vulnerable to stress: they exhibited social impairment and increased levels of serum CORT even after short-term CUMS for 2 weeks. Nicotine attenuated CUMS-induced 1) behavioral changes, such as decreased social interaction time and increased immobility time, and 2) increased levels of serum CORT by inhibiting the increase in corticotropin-releasing hormone. MLA inhibited the attenuating effect of nicotine, but not DHβE.

Discussion & Conclusions: Our results suggest that CUMS-induced 1) behavioral changes and 2) the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression, and that KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Taken together, α7nACh receptor could be an attractive new target for MDD.