Plasticity in the glutamatergic synapses on striatal medium spiny neurons (MSNs) is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse.Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment.In the present work,we found that the negative reinforcement learning,escaping mild foot-shocks by correct nose-poking,was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice.Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1 (D1) receptor (D1-MSNs).However,24 h after the cocaine exposure,the potentiation required for reinforcement learning was dis-rupted.Specific manipulation of the activity of striatal D1-MSNs in D 1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal Dl-cre mice,but inhibition of these neurons reversed the rein-forcement learning impairment induced by cocaine.The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.