Drugs of abuse and stress induce a common synaptic adaptation in dopamine neurons. This study shows that both drugs of abuse and acute stress increase the strength of excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with low abuse potential do not cause this change. The synaptic effects of stress, but not cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These findings suggest that synaptic plasticity in dopamine neurons may be a key neural adaptation contributing to addiction and its interaction with stress, making it a potential therapeutic target for reducing addiction risk. The study also demonstrates that various drugs of abuse, including cocaine, amphetamine, morphine, nicotine, and ethanol, all cause similar synaptic changes. Additionally, acute stress also increases synaptic strength on midbrain dopamine neurons, indicating that this synaptic adaptation may play a role in drug seeking and relapse. The results suggest that enhancing synaptic strength on dopamine neurons may contribute to the reinforcing and addictive properties of drugs, as well as the effects of stress on drug seeking and relapse. The study provides evidence that synaptic plasticity in dopamine neurons is a key mechanism underlying addiction and its interaction with stress.Drugs of abuse and stress induce a common synaptic adaptation in dopamine neurons. This study shows that both drugs of abuse and acute stress increase the strength of excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with low abuse potential do not cause this change. The synaptic effects of stress, but not cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These findings suggest that synaptic plasticity in dopamine neurons may be a key neural adaptation contributing to addiction and its interaction with stress, making it a potential therapeutic target for reducing addiction risk. The study also demonstrates that various drugs of abuse, including cocaine, amphetamine, morphine, nicotine, and ethanol, all cause similar synaptic changes. Additionally, acute stress also increases synaptic strength on midbrain dopamine neurons, indicating that this synaptic adaptation may play a role in drug seeking and relapse. The results suggest that enhancing synaptic strength on dopamine neurons may contribute to the reinforcing and addictive properties of drugs, as well as the effects of stress on drug seeking and relapse. The study provides evidence that synaptic plasticity in dopamine neurons is a key mechanism underlying addiction and its interaction with stress.