The anaesthetic drug ketamine also has a rapid antidepressant effect. Although ketamine is known to block N-methyl-D-aspartate (NMDA) receptors, its exact target—which brain region and which cell groups—has remained elusive. Yang et al. found that neuronal burst firing in a single brain region called the lateral habenula drove robust depressive-like behaviors. These behaviors could be rapidly blocked by local ketamine infusion. Instead of acting on GABAergic neurons as previously suggested, ketamine blocked glutamatergic neurons in the “anti-reward center” lateral habenula to disinhibit downstream dopaminergic and serotonergic neurons. Lateral habenula bursting strongly required the synergistic action of NMDA receptors and voltage-sensitive T-type calcium channels. The latter may therefore be another promising target for the development of new rapid-acting antidepressants.
