ABSTRACTBACKGROUNDCues predicting heroin delivery induce heroin seeking by initiating synaptic glutamate release in the nucleus accumbens core. The intensity of heroin seeking is negatively modulated by cue-induced increases in synaptic proximity of astrocytes. Glutamate-driven heroin seeking is also negatively regulated by compounds that promote glutamate uptake through the astrocytic transporter GLT-1. We hypothesized that the cue-induced increase in astrocyte synaptic proximity reduces heroin seeking by increasing GLT-1 synaptic proximity.METHODSRats were trained to self-administer heroin or sucrose before undergoing extinction and cued reinstatement of heroin or sucrose seeking. We used confocal microscopy to assess expression and co-registration of GLT-1 with the synaptic marker Synapsin I in the nucleus accumbens core.RESULTSExtinction from heroin, but not sucrose self-administration, downregulated GLT-1. Heroin cues increased surface expression of GLT-1 in parallel with heroin seeking, but counter to expectations, the increase was not proximal to synapses identified by Synapsin I. In fact, astroglia showing cue-induced increased surface expression of GLT-1 constituted a distinct subpopulation of astroglia from those showing increased synaptic proximity. Supporting discrete mechanisms, preventing cue-evoked increases in astrocyte synaptic proximity by knocking down the astroglial-selective actin binding protein ezrin did not impact cue-induced increases in GLT-1 surface expression.CONCLUSIONSOur data demonstrate that heroin-paired cues elicit two transient adaptations in astrocytes in the nucleus accumbens core, restoration of synaptic proximity and increased surface expression of GLT-1. Each adaptation occurs in largely non-overlapping subpopulations of astrocytes, but both adaptations appear to dampen reinstated heroin seeking.
∆9-Tetrahydrocannabinol Self-Administration Induces Cell-Type Specific Adaptations and cFOS Expression in the Nucleus Accumbens Core
