Sleep Regulates Incubation of Cocaine Craving

After withdrawal from cocaine, chronic cocaine users often experience persistent reduction in total sleep time, which is accompanied by increased sleep fragmentation resembling chronic insomnia. This and other sleep abnormalities have long been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here, we report that after prolonged withdrawal from cocaine selfadministration, rats exhibited persistent reductionin nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep, as well as increased sleep fragmentation. In an attempt to improve sleep after cocaine withdrawal, we applied chronic sleep restriction to the rats duringtheir active (dark) phase ofthe day, which selectively decreasedthe fragmentation of REM sleep duringtheir inactive (light) phase without changing NREM or the total amount of daily sleep. Animals with improved REM sleep exhibited decreased incubation of cocaine craving, a phenomenon depictingthe progressiveintensification of cocaine seeking after withdrawal. In contrast, experimentallyincreasing sleep fragmentation after cocaine self-administration expedited the development of incubation of cocaine craving. Incubation of cocaine craving is partially mediated by progressive accumulation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). After withdrawal from cocaine, animals with improved REM sleep exhibited reduced accumulation of CP-AMPARs in the NAc, whereas increasing sleep fragmentation accelerated NAc CP-AMPAR accumulation. These results reveal a potential molecular substratethat can be engaged by sleepto regulate cocaine craving and relapse, anddemonstrate sleep-basedtherapeutic opportunitiesfor cocaine addiction.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588606/pdf/zns13300.pdf