Opioid exposure is known to cause transcriptomic changes in the nucleus accumbens (NAc). However, no studies to date have investigated cell type-specific transcriptomic changes associated with volitional opioid taking. Here, we use single nucleus RNA sequencing (snRNAseq) to comprehensively characterize cell type-specific alterations of the NAc transcriptome in rats self-administering morphine. One cohort of male Brown Norway rats was injected with acute morphine (10 mg/kg, i.p.) or saline. A second cohort of rats was allowed to self-administer intravenous morphine (1.0 mg/kg/infusion) for 10 consecutive days. Each morphine-experienced rat was paired with a yoked saline control rat. snRNAseq libraries were generated from NAc punches and used to identify cell type-specific gene expression changes associated with volitional morphine taking. We identified 1106 differentially expressed genes (DEGs) in the acute morphine group, compared to 2453 DEGs in the morphine self-administration group, across 27 distinct cell clusters. Importantly, we identified 1329 DEGs that were specific to morphine self-administration. DEGs were identified in novel clusters of astrocytes, oligodendrocytes, and D1R- and D2R-expressing medium spiny neurons in the NAc. Cell type-specific DEGs included Rgs9, Celf5, Oprm1, and Pde10a. Upregulation of Rgs9 and Celf5 in D2R-expressing neurons was validated by RNAscope. Approximately 85% of all oligodendrocyte DEGs, nearly all of which were associated with morphine taking, were identified in two subtypes. Bioinformatic analyses identified cell type-specific upstream regulatory mechanisms of the observed transcriptome alterations and downstream signaling pathways, including both novel and previously identified molecular pathways. These findings show that volitional morphine taking is associated with distinct cell type-specific transcriptomic changes in the rat NAc and highlight specific striatal cell populations and novel molecular substrates that could be targeted to reduce compulsive opioid taking.

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BACKGROUND Suicide attempts and suicide death disproportionately affect sexual and gender minority emerging adults (ages 18-24). However, suicide prevention strategies tailored for emerging adult sexual and gender minorities (EA-SGM) are not widely available. OBJECTIVE We will pilot test the combination of peer mentoring alongside an app-based intervention (Supporting Transitions to Adulthood and Reducing Suicide; STARS) designed to reduce suicidal ideation and behaviors. STARS will include suicide prevention content and will target positive affect, discrimination, and social support. After an in-person Safety Planning Intervention (SPI) with a clinician, STARS users can access content and activities to increase their intentions to use the SPI and overcome obstacles to its use. METHODS Guided by the RE-AIM framework, we will recruit and enroll a racially/ethnically diverse sample of 60 EA-SGM reporting past-month suicidal ideation. Using a Type 1 Effectiveness-Implementation Hybrid Design, participants will be randomized to receive the SP intervention (Control arm) or to receive the SP intervention alongside STARS (Intervention arm). We will follow participants for six months, with evaluations at 2, 4, and 6 months. Preliminary effectiveness outcomes (suicidal ideation and behavior) and hypothesized mechanisms of change (positive affect, coping with discrimination, and social support) will serve as our primary outcomes. Secondary outcomes include key implementation indicators, including participants’ willingness and adoption of SPI and STARS, and staff’s experiences delivering the program. RESULTS Research activities began in September 2021 and are ongoing. The University of Pennsylvania is the central institutional review board for this study (protocol #849500). Study recruitment began on October 14, 2022. CONCLUSIONS This project will be among the first tailored, mobile-based interventions for EA-SGM at risk for suicide. This project is responsive to documented gaps for this population: 1) approaches that address chosen family; 2) focus on a life-course perspective; 3) online approaches; and 4) focus on health equity and provision of additional services relevant to sexual minority youth. CLINICALTRIAL ClinicalTrials.gov NCT05018143