Ventral tegmental glutamate: a role in stress-, cue-, and cocaine-induced reinstatement of cocaine-seeking.

Ventral tegmental dopamine neurons are activated by primary rewards and, when such rewards are predictable' by reward-predicting stimuli. Glutamatergic input to the ventral tegmental area contributes to this activation: in animals trained to self-administer cocaine, cocaine-predictive cues trigger ventral tegmental glutamate release and dopaminergic activation. Mild footshock stress similarly causes glutamate release and dopaminergic activation in cocaine-trained but not cocaine-naïve animals. The ability of cocaine-predictive and stress-associated cues to activate the dopamine system and to trigger cocaine craving appears to be related to changes in the ability of glutamate to activate dopaminergic neurons, changes known to be caused by experience with stress or with drugs of abuse.