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In two preclinical studies, investigators examined mechanisms of ketamine actions in the lateral habenula, a region located next to the pineal stalk. Burst firing in the lateral habenula inhibits downstream mesolimbic activity in reward circuitry and, therefore, produces an antireward, depressive effect.
One study used rats that were genetically induced to have depression-like behaviors and chronically stressed mice with these behaviors (e.g., immobility in force swim test, lower sucrose preference). These animals, compared with control animals, showed greater burst firing of the lateral habenula, accompanied by greater activity at N-methyl-D-aspartate (NMDA) synapses, greater calcium influx, and greater potassium efflux. Ketamine blocked NM…