The nucleus accumbens is a forebrain region responsible for drug reward and goal-directed behaviors. It has long been believed that drugs of abuse exert their addictive properties on behavior by altering the strength of synaptic communication over long periods of time. To date, attempts at understanding the relationship between drugs of abuse and synaptic plasticity have relied on the high-frequency long-term potentiation model of T.V. Bliss & T. Lomo [(1973) Journal of Physiology, 232, 331-356]. We examined synaptic plasticity using spike-timing-dependent plasticity, a stimulation paradigm that reflects more closely the in vivo firing patterns of mouse core nucleus accumbens medium spiny neurons and their afferents. In contrast to other brain regions, the same stimulation paradigm evoked bidirectional long-term plasticity. The magnitude of spike-timing-dependent long-term potentiation (tLTP) changed with the delay between action potentials and excitatory post-synaptic potentials, and frequency, whereas that of spike-timing-dependent long-term depression (tLTD) remained unchanged. We showed that tLTP depended on N-methyl-d-aspartate receptors, whereas tLTD relied on action potentials. Importantly, the intracellular calcium signaling pathways mobilised during tLTP and tLTD were different. Thus, calcium-induced calcium release underlies tLTD but not tLTP. Finally, we found that the firing pattern of a subset of medium spiny neurons was strongly inhibited by dopamine receptor agonists. Surprisingly, these neurons were exclusively associated with tLTP but not with tLTD. Taken together, these data point to the existence of two subgroups of medium spiny neurons with distinct properties, each displaying unique abilities to undergo synaptic plasticity.