Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses

Exposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. Here, we explain this paradox by showing that both drugs induce NMDA receptor-containing, AMPA receptor (AMPAR)-silent excitatory synapses, but in distinct cell types through opposing cellular mechanisms: cocaine selectively induces silent synapses in D1-type neurons likely via a synaptogenesis process, whereas morphine induces silent synapses in D2-type neurons via internalization of AMPARs from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses become ‘unsilenced’ by recruiting AMPARs to strengthen excitatory inputs to D1-type neurons, while morphine-generated silent synapses are likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell-type specific, opposing mechanisms produce the same net shift of the balance between excitatory inputs to D1- and D2-type NAc neurons, which may underlie certain common alterations in NAc-based behaviors induced by both classes of drugs.