Volitional cocaine taking engages distinct medium spiny neuron and astrocyte transcriptional programs in the rat nucleus accumbens
Year: 2026
Type: preprint
Abstract: Cocaine use disorder (CUD) remains a major public health concern with no FDA-approved pharmacotherapy, underscoring the need to define the cellular and molecular adaptations produced by voluntary cocaine taking. The nucleus accumbens (NAc) is a key substrate for cocaine reinforcement and drug-seeking behavior, but interpretation of the functional role of its cellular heterogeneity in these behaviors is limited by past bulk transcriptomic studies. Here, we used single-nucleus RNA sequencing to profile the NAc of male and female rats that self-administered intravenous cocaine for 10 consecutive days versus yoked saline controls. After quality control, we analyzed 36,766 nuclei spanning major neuronal, glial, and vascular cell populations. Pseudobulk differential-expression analyses identified 478 cocaine-associated cell type-specific transcriptional changes that were concentrated in discrete medium spiny neuron (MSN) subclasses and astrocytes. D1 Ebf1 + MSNs showed the largest transcriptomic response, accounting for ∼40% of all differential-expression events, followed by D2 Stk32a + MSNs, astrocytes, and D1 Ppm1e + MSNs. These responses were largely cell type-specific, indicating that cocaine self-administration engages multiple molecular programs rather than a uniform accumbens-wide transcriptional signature. Immediate-early gene module-score analyses further revealed cocaine-associated activation states in select neuronal and non-neuronal cell populations, including D1 Ebf1 + MSNs, Drd3+ neurons, Sst+ interneurons, astrocytes, and oligodendrocytes. Gene-set, pathway, and upstream-regulator analyses nominated synaptic organization, axon guidance, RAS/MAPK signaling, NMDA receptor-associated signaling, and CREB-related transcriptional regulation as candidate mechanisms of cocaine-evoked plasticity. Together, these data provide a cell type-resolved resource for understanding how voluntary cocaine taking alters the rat NAc transcriptome and identifies discrete neuronal and glial cell populations for future mechanistic studies using preclinical CUD models.
Institution: University of Pennsylvania
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Single-nucleus transcriptomics in rat striatum following morphine administration and withdrawal, The role of central GLP-1 receptors in animal models of cocaine addiction, Cell-specific epigenetic and transcriptomic signatures of impulsivity and its regulation by stress in the nucleus accumbens, The role of central amylin receptor in opioid-mediated behaviors
OpenAlex ID: W7165793617