Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond

The neuroadaptation theory of addiction suggests that, similar to the development of most memories, exposure to drugs of abuse induces adaptive molecular and cellular changes in the brain which likely mediate addiction-related memories or the addictive state. Compared to other types of memories, addiction-related memories develop fast and last extremely long, suggesting that the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. We recently demonstrated that repeated exposure to cocaine generated a large portion of "silent" glutamatergic synapses within the nucleus accumbens (NAc). Silent glutamatergic synapses are synaptic connections in which only N-methyl-D-aspartic acid receptor (NMDAR)-mediated responses are readily detected whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are absent or highly labile. Extensive experimental evidence suggests that silent synapses are conspicuously efficient plasticity sites at which long-lasting plastic changes can be more easily induced and maintained. Thus, generation of silent synapses can be regarded as a process of metaplasticity, which primes the NAc for subsequent durable and robust plasticity for addiction-related memories. Focusing on silent synapse-based metaplasticity, this review discusses how key brain regions, such as the NAc, utilize the metaplasticity mechanism to optimize the plasticity machineries to achieve fast and durable plastic changes following exposure to cocaine. A summary of recent related results suggests that upon cocaine exposure, newly generated silent synapses may prime excitatory synapses within the NAc for long-term potentiation (LTP), thus setting the direction of future plasticity. Furthermore, because cocaine-generated silent synapses are enriched in NMDARs containing the NR2B subunit, the enhanced NR2B-signaling may set up a selective recruitment of certain types of AMPARs. Thus, silent synapse-based metaplasticity may lead to not only quantitative but also qualitative alterations in excitatory synapses within the NAc. This review is one of the first systematic analyses regarding the hypothesis that drugs of abuse induce metaplasticity, which regulates the susceptibility, the direction, and the molecular details of subsequent plastic changes. Taken together, metaplasticity ultimately serves as a key step in mediating cascades of addiction-related plastic alterations.