Substance P (SP) has been reported to produce effects on excitatory synaptic transmission in the nucleus accumbens (NAc) that are similar to those induced by cocaine. To address the question of whether SP serves as an endogenous mediator producing cocaine-like effects that are known to be D1-receptor-mediated, we tested the hypothesis that the effects of SP and cocaine on excitatory postsynaptic currents (EPSCs) in the NAc occlude one another. We report here that SP and SP5–11 actions occlude the effect of cocaine and vice versa. SP, SP5–11 and cocaine all depressed evoked, non-N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents in a concentration-dependent manner, with EC50 values of 0.12, 0.17 and 8.3 μm, respectively. Although cocaine was the least potent, it was most efficacious. SP, SP5–11 and cocaine all suppressed isolated NMDA receptor-mediated evoked EPSCs. SP5–11 (1 μm)-induced EPSC depression was blocked by the neurokinin-1 antagonist L732138 and by the D1-like receptor antagonist SCH23390. Pretreatment of slices with cocaine (30 μm) depressed the EPSC by 39.1% ± 4.8%. Application of SP or SP5–11 (1 μm) at the peak of the cocaine depressive effect on the EPSC did not produce any additional diminution of the response (5.7% ± 2.8%). In the reverse experiments, in which either SP or SP5–11 was applied first, subsequent application of cocaine at the peak of the peptide’s effect (30.3% ± 2.3%) produced a further but smaller depression (15.5% ± 3.6%) of the remaining EPSC. These data indicate that cocaine and SP produce similar effects on excitatory synaptic transmission in the NAc, and that their actions occlude one another. This suggests that SP may act like cocaine in its absence, and may be an endogenous trigger for the reward and behaviors associated with cocaine.