Drug seeking and drug self-administration in both animals and humans can be triggered by drugs of abuse themselves or by stressful events. Here, we demonstrate that in vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress both increase strength at excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal abuse potential do not cause this change. The synaptic effects of stress, but not of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These results suggest that plasticity at excitatory synapses on dopamine neurons may be a key neural adaptation contributing to addiction and its interactions with stress and thus may be an attractive therapeutic target for reducing the risk of addiction.

Drugs of abuse cause activation of the cyclic AMP response element binding protein (CREB) in the nucleus accumbens (NAc). Expression of active CREB in rat NAc medium spiny neurons (MSNs) increased their excitability, whereas dominant-negative CREB had the opposite effect. Decreasing excitability of NAc MSNs in vivo by overexpression of potassium channels enhanced locomotor responses to cocaine, suggesting that the increased NAc MSN excitability caused by CREB helped to limit behavioral sensitivity to cocaine.

Synaptic plasticity in the mesolimbic dopamine (DA) system is thought to contribute to the neural adaptations that mediate behavioral sensitization, a model for core aspects of addiction. Recently, it has been demonstrated that multiple classes of drugs of abuse, as well as acute stress, enhance strength at excitatory synapses on midbrain DA neurons. Here, we show that both the cocaine-and stress-induced synaptic enhancement involves an up-regulation of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This enhancement requires the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluRA as evidenced by its absence in mice lacking this subunit. The cocaine-elicited, but not the stress-elicited, synaptic potentiation in DA neurons was blocked by a D1-like receptor antagonist, indicating that the in vivo triggering mechanisms differ for these forms of experience-dependent synaptic modification. Surprisingly, behavioral sensitization to cocaine was elicited in GluRA(؊͞؊) mice, indicating that potentiation of excitatory synaptic transmission in DA neurons is not necessary for this form of behavioral plasticity. However, GluRA(؊͞؊) mice did not exhibit a conditioned locomotor response when placed in a context previously paired with cocaine, nor did they exhibit conditioned place preference in response to cocaine. We suggest that the drug-induced enhancement of excitatory synaptic transmission in midbrain DA neurons, although not required for behavioral sensitization per se, may contribute to the attribution of incentive value to drug-associated cues.