Heroin self-administration and extinction increases prelimbic cortical astroglia-synapse proximity and alters dendritic spine morphometrics that are reversed by N-acetylcysteine

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.

Neural signatures of opioid-induced risk-taking behavior in the prelimbic prefrontal cortex

“…Studies examining neural adaptations associated with repeated opioid exposure have revealed complex changes in PL neurons, including alterations in synaptic strength, dendritic spine morphology, glutamate receptor expression, among others [88][89][90][91][92][93]. Prior studies measuring the firing activity of PL neurons in response to acute opioid administration have resulted in contrasting findings; while some studies have reported increased excitability [42,94,95], others have shown inhibitory effects [96].…”

Accumbens Nitrergic Interneurons Drive the Cell Type-Specific Synaptic Plasticity Required for Cue-Induced Cocaine Seeking

“…Laser power and gain were first optimized and held relatively constant with minimal adjustments used only to maintain voxel saturation consistency between images. Images were deconvolved using Huygens software (Scientific Volume Imaging, Hillversum, Netherlands) prior to analysis 20 . Deconvolved Zstacks were imported to Bitplane Imaris (v9.0, Zurich, Switzerland).…”

“…Deconvolved Zstacks were imported to Bitplane Imaris (v9.0, Zurich, Switzerland). The filament module was used to semi-manually trace identified dendritic spines 16,20,35 . Dendritic spine head diameter (dH) was calculated using an automatic threshold set by Imaris, while dendritic spine density was calculated by normalizing the number of spines to the length of the dendrite (in µm).…”

“…This loss of glutamate tone engages presynaptic potentiation due to reduced activation of mGluR2/3 autoreceptors 9,10,17 Upon re-exposure to drug-predictive cues, spillover of glutamate into the extracellular space drives RST behavior and produces structural and functional adaptations in NAc medium spiny neurons (MSNs) associated with cue-induced drug seeking 2,6,12,13 . As mentioned above, the prelimbic cortex (PrL) delivers most of the glutamatergic input into the NAc associated with cocaine seeking, and this PrL to NAc pathway has been heavily implicated in the pathology of addiction 15,20,21 .…”

Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens

“…In addition to drug-dependent disruptions in astrocyte-mediated glutamate homeostasis, other investigations have revealed effects of rodent drug selfadministration on structural features of astrocytes (Adermark and Bowers, 2016;Testen et al, 2018;Kruyer et al, 2019;Namba et al, 2020;Siemsen et al, 2023). Further, synaptic colocalization of NAc astrocytes with both pre-and post-synaptic markers is decreased following cocaine or heroin self-administration and extinction or extended abstinence (Scofield et al, 2016;Testen et al, 2018;Kruyer et al, 2019;Kim et al, 2022), suggesting that NAc astrocytes exhibit decreased proximity to synaptic elements, perhaps contributing to impaired regulation of glutamate homeostasis.…”