Accumulating evidence indicates effects of illicit drug use on astrocytes. In particular, both the structure and function of nucleus accumbens (NAc) astrocytes are significantly impaired by rat cocaine self-administration. We recently reported that 10 days of long-access (6h/day) selfadministration access followed by 45 days of home cage access results in a ~40% reduction in surface area, volume, and synaptic colocalization of NAc astrocytes (Kim et al., 2022 eNeuro). In order to more fully interrogate the nature of these observed structural deficits, we developed a novel approach to perform three-dimensional branching complexity analysis of individual astrocytes. This analysis revealed cocaine-dependent reductions in the number of astrocyte branches and segments, with no effect on segment length, suggesting that reductions in morphometric features may be driven by branch loss rather than overall shrinkage of segments. In order to further explore whether loss of astrocyte peripheral processes might occur as a consequence of microglia pruning, we analyzed Iba-1 labeled microglia for evidence of astrocyte-derived Lck-GFP inclusions at withdrawal day 45 following cocaine versus saline selfadministration. We indeed observed inclusions of fluorescent astrocyte membranes within microglia, which were significantly more prevalent in the cocaine versus the saline group. Further, inclusions were positive for C3 complement protein, suggesting implication of a complement-dependent pathway in pruning. To confirm this, we blocked C3 receptor interactions using neutrophil inhibitory factor (NIF) peptide across abstinence following cocaine self-administration. Administration of intra-NAc NIF peptide significantly impaired behavioral measures of cocaine seeking and restored size and synaptic interactions of NAc astrocytes. These results collectively indicate that deficits in structural features of NAc astrocytes observed following cocaine self-administration are mediated by microglia pruning, and that inhibition of phagocytosis can reduce cocaine seeking behavior.


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