LY341495

LY341495 binds the orthosteric site of mGlu2 and mGlu3 receptors and blocks their activation, preventing the presynaptic autoreceptor feedback that normally limits glutamate release. Removing this brake increases glutamatergic transmission in cortical and limbic circuits, which is thought to trigger a burst of synaptic signalling and downstream mTOR-dependent plasticity resembling the mechanism of rapid antidepressants such as ketamine ^[1]. In a chronic unpredictable mild stress model of depression, LY341495 produced a dose-dependent, rapid antidepressant-like effect after both single and short repeated dosing ^[1].

A particularly notable finding is that a non-effective low dose of LY341495 combined with a non-effective low dose of ketamine reversed stress-induced behavioural deficits, with evidence of mTOR pathway activation, suggesting that mGlu2/3 antagonism could allow the antidepressant dose of ketamine to be lowered while avoiding its dissociative and hyperlocomotor side effects ^[1]. Separately, LY341495 has been used to demonstrate the role of mGlu2/3 receptors in the prelimbic prefrontal cortex in stress resilience and vulnerability, where local antagonism rapidly relieved social avoidance in susceptible mice ^[2]. These results have made LY341495 a central tool in the search for glutamatergic antidepressants and in dissecting stress-circuit pharmacology ^[1][2].

As a research compound LY341495 has no human safety profile and is used exclusively in preclinical settings. In animal studies the low-dose combination with ketamine notably avoided the hyperactivity and memory disruption seen with higher ketamine doses, but the antagonist itself increases excitatory tone, which theoretically carries excitotoxic or proconvulsant considerations at high exposure. It is strictly investigational and not intended for human consumption.

LY341495 was reported by Eli Lilly in the late 1990s as the most potent and selective group II metabotropic glutamate antagonist available, quickly becoming the field standard for blocking mGlu2/3 receptors. With the emergence of the rapid-antidepressant field catalysed by ketamine, LY341495 gained renewed prominence as a tool to demonstrate that mGlu2/3 antagonism could produce ketamine-like effects. It continues to appear in a large body of depression and stress-circuit research.

LY341495 is one of the most widely cited pharmacological tools in metabotropic glutamate research and the default antagonist for probing mGlu2/3 function. It is highly regarded for its selectivity and reliability, and its role in demonstrating ketamine-like antidepressant mechanisms has kept it central to translational neuroscience. It is understood as a research reagent rather than a therapeutic or consumer product.