Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.21.108530v1?rss=1 Authors: Siemsen, B. M., Hooker, K. N., McFaddin, J. A., Carpenter, E. A., Prescott, M. E., Brock, A. G., Leath, M. N., McGinty, J. F., Scofield, M. D. Abstract: Both clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission underlie heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce linked molecular and cellular adaptations in both astrocytes and neurons in the nucleus accumbens (NA) core that are required for cued relapse. For example, decreased expression of the glutamate transporter GLT-1 and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate overflow from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Importantly, normalizing heroin-induced GLT-1 downregulation prevents glutamate overflow, medium spiny neuron plasticity, and relapse. Surprisingly, little is known about heroin-induced alterations in cortical astroglia and their interaction with neurons. Here we show that heroin SA followed by extinction leads to increased astrocyte complexity and association with synaptic markers in the PrL cortex in male Sprague-Dawley rats. Enhanced astroglial complexity and synaptic interaction were reversed during extinction by repeated treatment with N-acetylcysteine (NAC), an antioxidant drug previously shown to inhibit heroin seeking. We also show that dendritic spines of PrL cortical neurons projecting to the NAcore are enlarged, yet the density of spines is decreased, after extinction from heroin SA. Repeated NAC treatment prevented the decrease in spine density but not dendritic spine expansion. These results reveal circuit-level adaptations in cortical dendritic spine morphology that are related to heroin-induced alterations in astrocyte complexity and association at synapses and demonstrate that NAC reverses cortical heroin-induced adaptations in multiple cell types. Copy rights belong to original authors. Visit the link for more info