Response dynamics of midbrain dopamine neurons and serotonin neurons to heroin, nicotine, cocaine, and MDMA

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.

Study at a glance

Abstract

Abstract Heroin, nicotine, cocaine, and MDMA are abused by billions of people. They are believed to target midbrain dopamine neurons and/or serotonin neurons, but their effects on the dynamic neuronal activity remain unclear in behaving states. By combining cell-type-specific fiber photometry of Ca 2+ signals and intravenous drug infusion, here we show that these four drugs of abuse profoundly modulate the activity of mouse midbrain dopamine neurons and serotonin neurons with distinct potency and kinetics. Heroin strongly activates dopamine neurons, and only excites serotonin neurons at higher doses. Nicotine activates dopamine neurons in merely a few seconds, but produces minimal effects on serotonin neurons. Cocaine and MDMA cause long-lasting suppression of both dopamine neurons and serotonin neurons, although MDMA inhibits serotonin neurons more profoundly. Moreover, these inhibitory effects are mediated through the activity of dopamine and serotonin autoreceptors. These results suggest that the activity of dopamine neurons and that of serotonin neurons are more closely associated with the drug's reinforcing property and the drug's euphorigenic property, respectively. This study also shows that our methodology may facilitate further in-vivo interrogation of neural dynamics using animal models of drug addiction.