Coadministration of scopolamine and mGlu2 NAM VU6001966 as a novel antidepressant approach: Lowering effective dose and reducing cognitive side effects

Psychopharmacology (Berl). 2025 Oct 13. doi: 10.1007/s00213-025-06916-6. Online ahead of print.

ABSTRACT

RATIONALE: Scopolamine, whose rapid and sustained antidepressant effects were first described nearly two decades ago, is associated with significant adverse effects that limit its clinical use. A safer alternative may involve coadministration of scopolamine at lower doses with other compounds that exhibit antidepressant properties. Growing evidence highlights the potential of group II metabotropic glutamate (mGlu) receptors as targets for depression treatment.

OBJECTIVES: This study aimed to evaluate whether the mGlu2 receptor NAM, VU6001966, can enhance the antidepressant-like effects of a subeffective dose of scopolamine in a mouse model of depression and to explore the underlying mechanism.

METHODS: Unpredictable chronic mild stress (UCMS) was employed as an animal model of depression. Behavioral tests assessing anhedonia-, apathy-, and helplessness-like states were used to evaluate the effects of a four-day coadministration of scopolamine and VU6001966. The impact of the drug combination on spatial and non-spatial learning was assessed in both naïve and stressed mice. Protein expression levels in the prefrontal cortex (PFC) and hippocampus were measured via Western blotting. Electrophysiological recordings in the medial PFC (mPFC) were conducted to assess excitatory synaptic transmission and long-term potentiation (LTP).

RESULTS: Subchronic VU6001966 treatment dose-dependently alleviated stress-induced depressive-like behaviors in mice. Moreover, a subeffective dose of VU6001966 potentiated the effects of a subeffective dose of scopolamine, significantly reducing UCMS-induced apathy- and anhedonia-like behaviors. Behavioral effects of the AMPA receptor antagonist NBQX and the TrkB receptor antagonist ANA-12 suggest that both AMPA and TrkB receptors contribute to the antidepressant-like actions of scopolamine combined with VU6001966. Consistent with these findings, Western blot analysis revealed accompanying changes in the pTrkB/TrkB ratio in the PFC. The combination of scopolamine and VU6001966 did not impair cognitive function or locomotor activity. However, electrophysiological recordings did not reveal any improvement in UCMS-induced impairments in excitatory synaptic transmission or LTP in the mPFC.

CONCLUSIONS: Coadministration of scopolamine with the mGlu2 NAM VU6001966 may offer a promising therapeutic strategy for the treatment of depression. Further studies are needed to clarify the underlying mechanisms and confirm its efficacy.

PMID:41081840 | DOI:10.1007/s00213-025-06916-6