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Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice.

ABSTRACT: Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following abstinence, and relapse. Bioinformatics analysis of this rich dataset identified numerous patterns of transcriptional regulation, with both region-specific and pan-circuit biological domains affected by heroin. Integration of RNA-seq data with OUD-relevant behavioral outcomes uncovered region-specific molecular changes and biological processes that predispose to OUD vulnerability. Comparisons with human OUD RNA-seq and genome-wide association study data revealed convergent molecular abnormalities and gene candidates with high therapeutic potential. These studies outline molecular reprogramming underlying OUD and provide a foundational resource for future investigations into mechanisms and treatment strategies.

SUBMITTER: Browne CJ

PROVIDER: S-EPMC10256172 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice.

Browne Caleb J CJ Futamura Rita R Minier-Toribio Angélica A Hicks Emily M EM Ramakrishnan Aarthi A Martínez-Rivera Freddyson J FJ Estill Molly M Godino Arthur A Parise Eric M EM Torres-Berrío Angélica A Cunningham Ashley M AM Hamilton Peter J PJ Walker Deena M DM Huckins Laura M LM Hurd Yasmin L YL Shen Li L Nestler Eric J EJ

Science advances 20230609 23

Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-se ...[more]

PMID: 37294757

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Project description:Recent progress in psychiatric research has highlighted neuroinflammation in the pathophysiology of opioid use disorder (OUD), suggesting that heightened immune responses in the brain may exacerbate opioid-related mechanisms. However, the molecular mechanisms resulting from neuroinflammation that impact opioid-induced behaviors and transcriptional pathways remain poorly understood. In this study, we have begun to address this critical knowledge gap by exploring the intersection between neuroinflammation and exposure to the opioid heroin, utilizing lipopolysaccharide (LPS)-induced neuroinflammation, to investigate transcriptional changes in the nucleus accumbens (NAc), an essential region in the mesolimbic dopamine system that mediates opioid reward. By integrating RNA sequencing with bioinformatic and statistical analyses, we observed significant transcriptional overlaps between neuroinflammation and experimenter-administered heroin exposure in the NAc. Furthermore, we identified a subset of NAc genes synergistically regulated by LPS and heroin, suggesting that LPS history may exacerbate some heroin-induced molecular neuroadaptations. We extended our findings to examine the impact of neuroinflammatory history on responsiveness to heroin in a locomotor sensitization assay and observed LPS-induced exacerbation of heroin sensitization, indicating that neuroinflammation may increase sensitivity to opioids' behavioral effects. Lastly, we performed comparative analysis of the NAc transcriptional profiles of LPS-heroin rats with those obtained from voluntary heroin intake in a rat model of heroin self-administration (SA) and published human OUD datasets. We observed significant convergence of the three datasets and identified transcriptional patterns in the preclinical models that recapitulated human OUD neuropathology, highlighting the utility of preclinical models to further investigate molecular mechanisms of OUD pathology. Overall, our study elucidates transcriptional interconnections between neuroinflammation and heroin exposure, and also provides evidence of the behavioral ramifications of such interactions. By bridging the gap between neuroinflammation and heroin exposure at the transcriptional level, our work provides valuable insights for future research aimed at mitigating the influence of inflammatory pathways in OUD.

Project description:Recently, Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow's et al. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of 10 heroin addicts undergoing protracted abstinence (average 16.9 months). In a randomized placebo-controlled crossover study of KB220Z, five subjects completed a triple-blinded experiment in which the subject, the person administering the treatment, and the person evaluating the response to treatment were blinded to the treatment that any particular subject was receiving. In addition, nine subjects were genotyped utilizing the GARSDX™ test. We preliminarily report that KB220Z induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration. Furthermore, KB220Z also reduced resting-state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all 10 abstinent heroin-dependent subjects, we observed that three brain regions of interest were significantly activated from resting state by KB220Z compared to placebo (p < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. These results and other quantitative electroencephalogy (qEEG) study results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results, and confirmation with additional research and ongoing rodent and human studies of KB220Z is required.

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Dataset Information

Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice.

Publications

Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice.

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