Coadministration of scopolamine and mGlu2 receptor negative allosteric modulator VU6001966 as a potential therapeutic approach for depression: Rat frontal cortex neurochemistry and behavior.

Clinical studies provide evidence that scopolamine, a nonselective antagonist of muscarinic cholinergic receptors, exerts rapid and prolonged antidepressant effects. However, its use as a psychiatric drug has been limited due to its significant adverse effects. A therapeutic option that could help reduce the adverse effects of scopolamine is its coadministration at lower doses with other substances with similar antidepressant properties. To address this issue, we have investigated the effect of a single acute coadministration of scopolamine and a negative allosteric modulator of the mGlu2 receptor VU6001966 on rat behavior using a forced swim test (FST) and locomotor activity test. The effect of given compounds on the extracellular levels of neurotransmitters in the rat frontal cortex (FCX) was examined using microdialysis in freely moving rats. Both scopolamine and VU6001966 induced dose-dependent antidepressant-like effects in the FST test without affecting locomotor activity. Furthermore, VU6001966 enhanced extracellular dopamine and serotonin levels while lowering glutamate, without affecting GABA level. Both scopolamine alone or in combination with VU6001966 increased dopamine, serotonin, and glutamate levels in the FCX, without affecting GABA levels. Our results suggest that coadministration of scopolamine with mGlu2 NAM might be a promising alternative to using scopolamine alone in depression therapy, potentially allowing for a lower therapeutically effective dose. The common mechanism underlying the observed behavioral effects of the tested drugs may be associated with the modulation of the serotoninergic, glutamatergic, and dopaminergic systems.