Four widely abused drugs—heroin, nicotine, cocaine, and MDMA—modulate the activity of midbrain dopamine and serotonin neurons in mice with distinct potency and timing. Heroin strongly activates dopamine neurons but excites serotonin neurons only at higher doses. Nicotine activates dopamine neurons within seconds and has minimal effect on serotonin neurons. Cocaine and MDMA cause long-lasting suppression of both neuron types, with MDMA more profoundly inhibiting serotonin neurons. These inhibitory effects depend on dopamine and serotonin autoreceptors. The findings suggest that dopamine neuron activity relates more to a drug's reinforcing property, while serotonin neuron activity relates more to its euphorigenic property.
Adenosine signaling is identified as the central mechanism underlying the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT). Experiments in mice using genetically encoded adenosine sensors and real-time optical recordings show that both therapies cause strong adenosine surges in mood-regulatory brain regions such as the medial prefrontal cortex and hippocampus. Disrupting A1 and A2A adenosine receptors genetically or pharmacologically abolishes the therapeutic effects, establishing adenosine's essential role. Ketamine increases adenosine by modulating cellular metabolism without causing neuronal hyperactivity. Newly developed ketamine derivatives that enhance adenosine signaling show improved antidepressant efficacy with fewer side effects. Acute intermittent hypoxia, a non-pharmacological intervention, also increases brain adenosine and produces antidepressant effects, paralleling ketamine and ECT.