Esketamine, a new antidepressant, works through a complex interaction with brain chemicals rather than a single target. In mice, esketamine increased movement and raised overall dopamine levels by slowing dopamine removal, not by boosting its release. It also reduced glutamate activity. However, it decreased spontaneous dopamine release events and blunted reward-triggered dopamine release, which lowered the mice's motivation to work for rewards. Some of these dopamine effects were partially blocked by naloxone, an opioid blocker, and depended on glutamate input. The findings suggest esketamine's effects on brain chemistry vary by brain circuit and behavioral state.
Adolescent mice treated with THC, the main psychoactive compound in cannabis, later showed impaired social interaction and sensorimotor gating deficits similar to those seen in heavy human cannabis users. The exposure caused long-term disruption of connectivity between the cortex and striatum, which correlated with social problems in adulthood. Molecular changes in the striatum altered the balance among dopamine D2, adenosine A2A, and cannabinoid CB1 receptors, key regulators of the brain's reward system. These results help explain how heavy adolescent cannabis use may increase the risk of psychosis.