Rapamycin-sensitive mTORC1 signaling in the medial prefrontal cortex contributes to the antidepressant-like behavioral effects of shikimic acid in mice.

AIMS: Major depressive disorder (MDD) represents a major contributor to disability, yet currently prescribed monoamine-based antidepressants are limited by modest therapeutic efficacy and delayed clinical onset. Recent studies have demonstrated that ketamine, an N-methyl-d-aspartate receptor antagonist, rapidly engages mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex (mPFC), critically linked to its fast-acting antidepressant actions. Shikimic acid (SA), a natural compound widely found in various plants, has been reported to exhibit mTORC1-related signaling activity. In this study, we investigated whether SA induces antidepressant-like behavioral responses through mTORC1-related signaling in the mPFC.

MATERIALS AND METHODS: Antidepressant-like effects of SA were assessed in male and female outbred ICR and inbred C57BL/6 J mice using the forced swim test (FST), with locomotor activity evaluated in the open field test. The role of mTORC1 signaling was evaluated by systemic and intra-mPFC administration of the mTORC1 inhibitor rapamycin. The antidepressant-like effects of SA were further examined in ovariectomized (OVX) mice, a model of menopause-associated depression.

KEY FINDINGS: SA significantly reduced immobility in the FST in naïve male but not female ICR mice, and this effect was abolished by systemic and intra-mPFC rapamycin. Comparable effects were observed in naïve male, but not female, C57BL/6 J mice. SA also reversed OVX-induced increase in immobility, and this effect was completely prevented by intra-mPFC rapamycin.

SIGNIFICANCE: These findings suggest that SA exerts antidepressant-like effects via rapamycin-sensitive mTORC1-dependent mechanisms within the mPFC. Our results support SA as a candidate compound targeting mPFC mTORC1-related signaling for novel rapid-acting antidepressants.