AbstractSmall fluctuations in striatal glutamate and dopamine are required to establish goal‐directed behaviors and motor learning, while large changes appear to underlie many neuropsychological disorders, including drug dependence and Parkinson's disease. A better understanding of how variations in neurotransmitter availability can modify striatal circuitry will lead to new therapeutic targets for these disorders. Here, we examined dopamine‐induced plasticity in prefrontal cortical projections to the nucleus accumbens (NAc) core. We combined behavioral measures of male mice, presynaptic optical studies of glutamate release kinetics from prefrontal cortical projections, and postsynaptic electrophysiological recordings of spiny projection neurons within the NAc core. Our data show that repeated amphetamine promotes long‐lasting but reversible changes along the corticoaccumbal pathway. In saline‐treated mice, coincident cortical stimulation and dopamine release promoted presynaptic filtering by depressing exocytosis from glutamatergic boutons with a low‐probability of release. The repeated use of amphetamine caused a frequency‐dependent, progressive, and long‐lasting depression in corticoaccumbal activity during withdrawal. This chronic presynaptic depression was relieved by a drug challenge which potentiated glutamate release from synapses with a low‐probability of release. D1 receptors generated this synaptic potentiation, which corresponded with the degree of locomotor sensitization in individual mice. By reversing the synaptic depression, drug reinstatement may promote allostasis by returning corticoaccumbal activity to a more stable and normalized state. Therefore, dopamine‐induced synaptic filtering of excitatory signals entering the NAc core in novice mice and paradoxical excitation of the corticoaccumbal pathway during drug reinstatement may encode motor learning, habit formation, and dependence.