Antidepressant-like effects of kynurenic acid in a modified forced swim test

Kynurenic acid (KYNA) is an L-tryptophan metabolite with neuromodulatory activities, regulating the release of neurotransmitters such as glutamate, dopamine (DA), and acetylcholine (Ach). Dysregulation of the kynurenine pathway has been associated with neurodegenerative, neurological, and psychological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, major depressive disorder, and schizophrenia.

The antidepressant-like effects of KYNA were studied with a modified mouse forced swimming test (FST), and the potential involvement of the serotonin (SER), norepinephrine, DA, Ach, N-methyl-D-aspartate, or gamma-aminobutyric acid subunit A (GABA_A) receptors in its antidepressant-like effect was assayed by modified combination mouse FST. In combination studies, the mice were pretreated with the respective receptor antagonist, cyproheptadine (CPH), phenoxybenzamine, yohimbine, propranolol, haloperidol (HPD), atropine, MK-801, or bicuculline (BCL).

The FST revealed that KYNA reversed immobility, climbing, and swimming times, suggesting the antidepressant-like effects of KYNA. Furthermore, the combination studies showed that CPH prevented the antidepressant-like effects of KYNA on immobility, climbing, and swimming times, whereas HPD reduced climbing time and BCL influenced immobility and climbing times and prevented the effects of KYNA on swimming time.

The results demonstrated, for the first time, the presence of antidepressant-like effects of KYNA in a modified mouse FST. Furthermore, modified combination FST showed that the antidepressant-like actions of KYNA strongly interacted with 5-hydroxytryptamine type 2 SER-ergic receptors, weakly interacted with D₂, D₃, D₄ DA-ergic receptors, and interacted moderately with GABA_A receptors.