Network-Based Discovery of Opioid Use Vulnerability in Rats Using the Bayesian Stochastic Block Model

Opioid use disorder is a psychological condition that affects over 200,000 people per year in the U.S., causing the Centers for Disease Control and Prevention to label the crisis as a rapidly spreading public health epidemic. The behavioral relationship between opioid exposure and development of opioid use disorder (OUD) varies greatly between individuals, implying existence of sup-populations with varying degrees of opioid vulnerability. However, effective pre-clinical identification of these sub-populations remains challenging due to the complex multivariate measurements employed in animal models of OUD. In this study, we propose a novel non-linear network-based data analysis workflow that employs seven behavioral traits to identify opioid use sub-populations and assesses contributions of behavioral variables to opioid vulnerability and resiliency. Through this analysis workflow we determined how behavioral variables across heroin taking, refraining and seeking interact with one another to identify potentially heroin resilient and vulnerable behavioral sub-populations. Data were collected from over 400 heterogeneous stock rats in two geographically distinct locations. Rats underwent heroin self-administration training, followed by a progressive ratio and heroin-primed reinstatement test. Next, rats underwent extinction training and a cue-induced reinstatement test. To enter the analysis workflow, we integrated data from different cohorts of rats and removed possible batch effects. We then constructed a rat-rat similarity network based on their behavioral patterns and implemented community detection on this similarity network using a Bayesian degree-corrected stochastic block model to uncover sub-populations of rats with differing levels of opioid vulnerability. We identified three statistically distinct clusters corresponding to distinct behavioral sub-populations, vulnerable, resilient and intermediate for heroin use, refraining and seeking. We implement this analysis workflow as an open source R package, named mlsbm.

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Network-Based Discovery of Opioid Use Vulnerability in Rats Using the Bayesian Stochastic Block Model

10.1101/2021.06.30.450568 ◽

2021 ◽

Author(s):

Carter Allen ◽

Brittany N Kuhn ◽

Nazzareno Cannella ◽

Ayteria D Crow ◽

Analyse T Roberts ◽

...

Keyword(s):

Progressive Ratio ◽

Opioid Use Disorder ◽

Heroin Addiction ◽

Opioid Use ◽

Self Administration ◽

Block Model ◽

Similarity Network ◽

Stochastic Block Model ◽

Analysis Workflow ◽

Reinstatement Test

Opioid use disorder is a psychological condition that affects over 200,000 people per year in the U.S., causing the Centers for Disease Control and Prevention to label the crisis as a rapidly spreading public health epidemic. It has been found that the behavioral relationship between opioid exposure and development of opioid use disorder varies greatly between individuals, implying existence of sup-populations with varying degrees of opioid vulnerability. In this study, we assessed several behavioral variables across heroin taking, refraining and seeking to establish how these factors interact with one another resulting in a heroin dependent, resilient, or vulnerable behavioral phenotype. Over 400 (male and female) heterogeneous stock rats were used in these two studies, and data were collected from two geographically distinct locations. Rats underwent heroin self-administration training, followed by a progressive ratio and heroin-primed reinstatement test. Next, rats underwent extinction training and a cue-induced reinstatement test. To assess how these variables contribute to heroin addiction vulnerability, we developed a network-based data analysis workflow. Specifically, we integrated different cohorts of rats, remove possible batch effects, and constructed a rat-rat similarity network based on their behavioral patterns. We then implemented community detection on this similarity network using a Bayesian degree-corrected stochastic block model to uncover sub-populations of rats with differing levels of opioid vulnerability. We discovered three distinct behavioral sub-populations, each with significantly different behavioral outcomes that allowed for unique characterization of each cluster in terms of vulnerability to opioid use and seeking. We implement this analysis workflow as an open source R package, named mlsbm.

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Prolonged Withdrawal from Escalated Oxycodone is Associated with Increased Expression of Glutamate Receptors in the Rat Hippocampus

10.1101/2020.12.20.423680 ◽

2020 ◽

Author(s):

Aaron J Salisbury ◽

Christopher A Blackwood ◽

Jean Lud Cadet

Keyword(s):

Glutamate Receptors ◽

Molecular Mechanisms ◽

Quantitative Polymerase Chain Reaction ◽

Opioid Use Disorder ◽

Mrna Levels ◽

Opioid Use ◽

Self Administration ◽

Lever Pressing ◽

Polymerase Chain ◽

Long Access

People suffering from opioid use disorder (OUD) exhibit cognitive dysfunctions. Here, we investigated potential changes in the expression of glutamate receptors in rat hippocampi at 2 hours and 31 days after the last session of oxycodone self-administration (SA). RNA extracted from the hippocampus was used in quantitative polymerase chain reaction (qPCR) analyses. Rats, given long-access (9 hours per day) to oxycodone (LgA), took significantly more drug than rats exposed to short-access (3 hours per day) (ShA). In addition, LgA rats could be further divided into higher oxycodone taking (LgA-H) or lower oxycodone taking (LgA-L) groups, based on a cut-off of 50 infusions per day. LgA rats, but not ShA, rats exhibited incubation of oxycodone craving. In addition, LgA rats showed increased mRNA expression of GluA1-3 and GluN2a-c subunits as well as Grm3, Grm5, Grm6 and Grm8 subtypes of glutamate receptors after 31 days but not after 2 hours of stopping the SA experiment. Changes in GluA1-3, Grm6, and Grm8 mRNA levels also correlated with increased lever pressing (incubation) after long periods of withdrawal from oxycodone. More studies are needed to elucidate the molecular mechanisms involved in altering the expression of these receptors during withdrawal from oxycodone and/or incubation of drug seeking.

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Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA–GABA transmission in highly addicted rats

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1915143117 ◽

2020 ◽

Vol 117 (4) ◽

pp. 2140-2148 ◽

Cited By ~ 3

Author(s):

Marsida Kallupi ◽

Lieselot L. G. Carrette ◽

Jenni Kononoff ◽

Leah C. Solberg Woods ◽

Abraham A. Palmer ◽

...

Keyword(s):

Molecular Mechanisms ◽

Opioid Use Disorder ◽

Central Nucleus ◽

Orphanin Fq ◽

Opioid Use ◽

Self Administration ◽

Endogenous Opioid ◽

Electrophysiological Recordings ◽

Gaba Transmission

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.

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Prolonged Withdrawal From Escalated Oxycodone Is Associated With Increased Expression of Glutamate Receptors in the Rat Hippocampus

Frontiers in Neuroscience ◽

10.3389/fnins.2020.617973 ◽

2021 ◽

Vol 14 ◽

Author(s):

Aaron J. Salisbury ◽

Christopher A. Blackwood ◽

Jean Lud Cadet

Keyword(s):

Glutamate Receptors ◽

Molecular Mechanisms ◽

Quantitative Polymerase Chain Reaction ◽

Opioid Use Disorder ◽

Mrna Levels ◽

Opioid Use ◽

Self Administration ◽

Lever Pressing ◽

Polymerase Chain ◽

Long Access

People suffering from opioid use disorder (OUD) exhibit cognitive dysfunctions. Here, we investigated potential changes in the expression of glutamate receptors in rat hippocampi at 2 h and 31 days after the last session of oxycodone self-administration (SA). RNA extracted from the hippocampus was used in quantitative polymerase chain reaction analyses. Rats, given long-access (9 h per day) to oxycodone (LgA), took significantly more drug than rats exposed to short-access (3 h per day) (ShA). In addition, LgA rats could be further divided into higher oxycodone taking (LgA-H) or lower oxycodone taking (LgA-L) groups, based on a cut-off of 50 infusions per day. LgA rats, but not ShA, rats exhibited incubation of oxycodone craving. In addition, LgA rats showed increased mRNA expression of GluA1-3 and GluN2a-c subunits as well as Grm3, Grm5, Grm6, and Grm8 subtypes of glutamate receptors after 31 days but not after 2 h of stopping the SA experiment. Changes in GluA1-3, Grm6, and Grm8 mRNA levels also correlated with increased lever pressing (incubation) after long periods of withdrawal from oxycodone. More studies are needed to elucidate the molecular mechanisms involved in altering the expression of these receptors during withdrawal from oxycodone and/or incubation of drug seeking.

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Drug-associated cues and drug dosage contribute to increased opioid seeking after abstinence

Scientific Reports ◽

10.1038/s41598-021-94214-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mary Tresa Zanda ◽

Gabriele Floris ◽

Stephanie E. Sillivan

Keyword(s):

Drug Dosage ◽

Opioid Use Disorder ◽

Drug Intake ◽

Opioid Use ◽

Self Administration ◽

Drug Seeking ◽

Drug Cues ◽

Rehabilitation Programs ◽

Key Factor ◽

Seeking Behavior

AbstractPatients with opioid use disorder experience high rates of relapse during recovery, despite successful completion of rehabilitation programs. A key factor contributing to this problem is the long-lasting nature of drug-seeking behavior associated with opioid use. We modeled this behavior in a rat drug self-administration paradigm in which drug-seeking is higher after extended abstinence than during the acute abstinence phase. The goal of this study was to determine the contribution of discrete or discriminative drug cues and drug dosage to time-dependent increases in drug-seeking. We examined heroin-seeking after 2 or 21 days of abstinence from two different self-administration cue-context environments using high or low doses of heroin and matched animals for their drug intake history. When lower dosages of heroin are used in discriminative or discrete cue protocols, drug intake history contributed to drug-seeking after abstinence, regardless of abstinence length. Incubation of opioid craving at higher dosages paired with discrete drug cues was not dependent on drug intake. Thus, interactions between drug cues and drug dosage uniquely determined conditions permissible for incubation of heroin craving. Understanding factors that contribute to long-lasting opioid-seeking can provide essential insight into environmental stimuli and drug-taking patterns that promote relapse after periods of successful abstinence.

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The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

10.1101/2020.04.25.061887 ◽

2020 ◽

Cited By ~ 1

Author(s):

Shayna L. O’Connor ◽

Jennifer E. Fragale ◽

Morgan H James ◽

Gary Aston-Jones

Keyword(s):

Drugs Of Abuse ◽

Therapeutic Potential ◽

Opioid Use Disorder ◽

Opioid Use ◽

Self Administration ◽

Drug Experience ◽

Reward Seeking ◽

Intermittent Access ◽

General Locomotor Activity ◽

Target Effects

AbstractThe orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD). Suvorexant (Belsomra™) is a dual orexin receptor 1/orexin receptor 2 (OxR1/OxR2) antagonist that is FDA-approved for the treatment of insomnia, and thus has the potential to be readily repurposed for the treatment of OUD. However, studies have yet to test the therapeutic potential of suvorexant with respect to reducing opioid-related behaviors. Accordingly, here we investigated the efficacy of suvorexant in reducing several addiction-relevant behaviors in fentanyl self-administrating rats. In rats with limited drug experience, suvorexant decreased motivation for fentanyl on a behavioral economics (BE) task. This effect was greatest in rats with the highest motivation for fentanyl. Suvorexant was even more effective at decreasing motivation for fentanyl following induction of a more robust addiction phenotype by intermittent access (IntA) self-administration of the opioid. Suvorexant also attenuated punished responding for fentanyl and reduced cued reinstatement in IntA rats. Suvorexant did not affect general locomotor activity or natural reward seeking, indicating that at the doses used here, suvorexant can be used to reduce drug seeking with limited sedative or off-target effects. Together, these results highlight the therapeutic potential of suvorexant, particularly in individuals with the severe OUD.

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Effects of lorcaserin on oxycodone self-administration and subjective responses in participants with opioid use disorder

Drug and Alcohol Dependence ◽

10.1016/j.drugalcdep.2020.107859 ◽

2020 ◽

Vol 208 ◽

pp. 107859 ◽

Cited By ~ 4

Author(s):

Laura Brandt ◽

Jermaine D. Jones ◽

Suky Martinez ◽

Jeanne M. Manubay ◽

Shanthi Mogali ◽

...

Keyword(s):

Opioid Use Disorder ◽

Opioid Use ◽

Self Administration ◽

Subjective Responses

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Acute Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Prevents Drug-Induced Heroin Seeking in Rats

10.1101/2021.09.15.460527 ◽

2021 ◽

Author(s):

Joaquin E Douton ◽

Nikhil K Acharya ◽

Brooke Stoltzful ◽

Dongxiao Sun ◽

Patricia S. Grigson ◽

...

Keyword(s):

Drugs Of Abuse ◽

Opioid Use Disorder ◽

Opioid Use ◽

Self Administration ◽

Drug Induced ◽

Locomotor Impairment ◽

Pretreatment Time ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Long Acting

Substance use disorder is a difficult disease to treat due to its relapsing nature. In the last decade, opioid use disorder has been a threat to public health, being declared an epidemic by the Centers for Disease Control and Prevention. This is a tragic situation, considering there are currently effective, yet not ideal, treatments to prevent relapse. Recent research has shown that hormones that modulate hunger and satiety also can modulate motivated behavior for drugs of abuse. For example, the short-acting analog of glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates homeostatic feeding, has been shown to reduce responding for rewarding stimuli such as food, cocaine, heroin and nicotine. Here, we tested the acute effects of the long-acting GLP-1 analog, liraglutide, on heroin seeking. We found that, in rats with heroin self-administration experience, subcutaneous (sc) administration of an acute dose of 0.3 mg/kg liraglutide was effective in preventing relapse after exposure to three major precipitators: drug-associated cues, stress, and the drug itself. However, the effects of the drug were contingent upon the pretreatment time, with the drug being fully effective when administered using a 6 h, rather than a 4 h pretreatment time. Finally, we confirmed that the reduction in drug seeking is not due to a locomotor impairment, as liraglutide did not significantly alter performance in a rotarod test. As such, this acute non-opioid treatment may serve as a new and effective bridge to treatment.

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The 5α-reductase inhibitor finasteride reduces opioid self-administration

10.1101/2020.09.15.291609 ◽

2020 ◽

Author(s):

Gabriel D. Bosse ◽

Roberto Cadeddu ◽

Gabriele Floris ◽

Ryan D. Farero ◽

Eva Vigato ◽

...

Keyword(s):

Reductase Inhibitor ◽

Antinociceptive Effect ◽

Dehydroepiandrosterone Sulfate ◽

Opioid Use Disorder ◽

Therapeutic Strategies ◽

Prostatic Hyperplasia ◽

Opioid Use ◽

Self Administration ◽

The Us ◽

Selection Of

AbstractOpioid use disorder (OUD) has become a leading cause of death in the US, yet current therapeutic strategies remain highly inadequate. To identify novel potential treatments for OUD, we screened a targeted selection of over 100 drugs, using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride did not interfere with the antinociceptive effect of opioids in rat models of neuropathic pain. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish, in a fashion akin to the effects of finasteride. Our results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new option for this disorder.

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