The study investigates the synaptic adaptations in midbrain dopamine (DA) neurons triggered by drugs of abuse and acute stress. The researchers found that both in vivo administration of drugs with different molecular mechanisms (such as cocaine, amphetamine, morphine, nicotine, and ethanol) and acute stress increase the strength of excitatory synapses on DA neurons. These changes are not observed with psychoactive but nonaddictive drugs like fluoxetine and carbamazepine. The synaptic effects of stress, but not cocaine, are blocked by the glucocorticoid receptor antagonist RU486, suggesting that stress-induced changes involve GR activation. The findings suggest that plasticity at excitatory synapses on DA neurons may be a key neural adaptation contributing to addiction and its interaction with stress, potentially making it an attractive therapeutic target for reducing the risk of addiction.The study investigates the synaptic adaptations in midbrain dopamine (DA) neurons triggered by drugs of abuse and acute stress. The researchers found that both in vivo administration of drugs with different molecular mechanisms (such as cocaine, amphetamine, morphine, nicotine, and ethanol) and acute stress increase the strength of excitatory synapses on DA neurons. These changes are not observed with psychoactive but nonaddictive drugs like fluoxetine and carbamazepine. The synaptic effects of stress, but not cocaine, are blocked by the glucocorticoid receptor antagonist RU486, suggesting that stress-induced changes involve GR activation. The findings suggest that plasticity at excitatory synapses on DA neurons may be a key neural adaptation contributing to addiction and its interaction with stress, potentially making it an attractive therapeutic target for reducing the risk of addiction.