Heroin Cue-Evoked Astrocytic Structural Plasticity at Nucleus Accumbens Synapses Inhibits Heroin Seeking

Background: Opioid addiction is a critical medical and social problem characterized by vulnerability to relapse. Glutamatergic synapses in the nucleus accumbens regulate the motivation to relapse to opioid use and down-regulation of glutamate transporters on astroglial processes adjacent to accumbens synapses contributes to heroin seeking induced by cues. However, it is not known how astroglial processes themselves respond to heroin cues or if changes in astroglial morphology are necessary for heroin seeking. Methods: Male Sprague-Dawley rats (n=62) were trained to self-administer heroin or sucrose and were reinstated by heroin- or sucrose-conditioned cues. Astroglial proximity to accumbens synapses was estimated using a confocal-based strategy and the association between digitally isolated astroglia and the presynaptic marker Synapsin I was quantified. To determine the functional consequence of astroglial morphological plasticity on cued heroin seeking, a morpholino antisense strategy was used to knock down expression of the actin binding protein ezrin, which is expressed almost exclusively in peripheral astrocyte processes in the adult rat brain. Results: After heroin extinction, there was an enduring reduction in synaptic proximity by astroglia. Synaptic proximity was restored during 15 min of cued heroin seeking, but returned to extinction levels by 120 min. Extinction from sucrose self-administration and reinstated sucrose-seeking induced no changes in astroglial synaptic association. Ezrin knockdown reduced astroglial association with synapses and potentiated cued heroin seeking. Conclusions: Cue-induced heroin seeking transiently increased synaptic proximity of accumbens astrocytes. Surprisingly, the re-association of astroglia with synapses was compensatory, and preventing cue-induced morphological plasticity in astrocytes potentiated heroin seeking.