Previously used as a horse tranquilizer and party drug, ketamine has reinvented itself over the past few years as a treatment for depression. Impressively, the drug has been shown to alleviate depressive symptoms in as little as 24 hours, which represents a major improvement on traditional medications like selective serotonin reuptake inhibitors (SSRIs), which can take weeks or months to produce an effect. According to a new study in the journal Molecular Psychiatry, ketamine’s ability to provide such rapid relief may hinge on its capacity to inhibit a particular neurotransmitter called glutamate.

"Elevated glutamate release has been linked to stress, depression and other mood disorders, so lowered glutamate levels may explain some of the effects of ketamine," explained study author Per Svenningsson in a statement.

The idea that ketamine may somehow regulate the effects of glutamate is not new, although scientists have struggled to understand the influence that the drug exerts over this key neurotransmitter. Previous research has revealed that ketamine blocks a type of brain receptor known as NMDA glutamate receptors, thereby preventing brain cells from becoming overstimulated by glutamate. Separate studies, meanwhile, have indicated that ketamine’s rapid anti-depressant effects may be mediated by one of its metabolites called (2R,6R)-HNK, which binds to a different class of receptor known as AMPA receptors.

To understand how these various mechanisms interact with one another, the authors of the latest study injected mice with both ketamine and (2R,6R)-HNK. Doing so produced an immediate decrease in glutamate levels in the rodents’ brains, and also led to a reduction in depressive symptoms such as an unwillingness to swim when placed in water.

Further analysis revealed that both ketamine and (2R,6R)-HNK activated AMPA receptors on postsynaptic neurons, which normally receive glutamate released by presynaptic neurons. This caused a neurotransmitter called adenosine to be secreted back across the synapse and bind to receptors on presynaptic neurons, preventing them from releasing glutamate.

Within 30 minutes, the researchers detected a significant decrease in glutamate secretions in the animals’ brains. As a consequence, mice that had been genetically engineered to suffer from depression displayed an immediate increase in their desire to swim, thus confirming ketamine’s rapid anti-depressive effects.

However, when the researchers chemically blocked postsynaptic AMPA receptors, glutamate levels increased and mice no longer demonstrated reductions in depression. This finding corroborates the notion that both ketamine and (2R,6R)-HNK rely on AMPA receptors in order to curb the release of glutamate and attenuate depressive symptoms.

Summing up the significance of their work, the study authors suggest that these findings could open the door for the development of new anti-depressants that work via the same mechanism but do not produce any of the trippy side-effects for which ketamine is famous.