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  1. Artikel ; Online: Novelty preference does not predict trait cocaine behaviors in male rats.

    O'Connor, Shayna L / Aston-Jones, Gary / James, Morgan H

    Addiction neuroscience

    2022  Band 2

    Abstract: Heightened novelty seeking is a risk factor for the initiation of drug use and development of substance use disorders. In rats, novelty seeking can be examined by assessing preference for a novel environment. Some evidence indicates that high novelty ... ...

    Abstract Heightened novelty seeking is a risk factor for the initiation of drug use and development of substance use disorders. In rats, novelty seeking can be examined by assessing preference for a novel environment. Some evidence indicates that high novelty preferring (HNP) rats have higher drug intake compared to low novelty preferring (LNP) rats, although these data are mixed. Moreover, the extent to which the HNP phenotype can predict other initial drug behaviors, including economic demand for cocaine, has not been tested. Here, we screened a cohort (n=60) of male rats for novelty preference and several subsequent cocaine behaviors, including locomotor reactivity to a cocaine priming injection, acquisition of cocaine self-administration, as well as cocaine demand using a within-session behavioral economics procedure. Novelty preference did not correlate with cocaine behaviors, nor were there any differences between HNP and LNP rats identified using a median split strategy. Moreover, regression analyses indicated that novelty preference did not have predictive utility for any of the cocaine behaviors tested. Thus, the extent to which the novelty preference trait can predict initial cocaine-related behaviors in male rats may be limited. This is in contrast to the novel locomotor reactivity phenotype, which is strongly linked with initial cocaine intake, indicating that these traits are distinct and differentially predict cocaine behaviors in rats.
    Sprache Englisch
    Erscheinungsdatum 2022-03-23
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article
    ISSN 2772-3925
    ISSN (online) 2772-3925
    DOI 10.1016/j.addicn.2022.100013
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Machine learning models to predict ligand binding affinity for the orexin 1 receptor.

    Zhang, Vanessa Y / O'Connor, Shayna L / Welsh, William J / James, Morgan H

    Artificial intelligence chemistry

    2023  Band 2, Heft 1

    Abstract: The orexin 1 receptor (OX1R) is a G-protein coupled receptor that regulates a variety of physiological processes through interactions with the neuropeptides orexin A and B. Selective OX1R antagonists exhibit therapeutic effects in preclinical models of ... ...

    Abstract The orexin 1 receptor (OX1R) is a G-protein coupled receptor that regulates a variety of physiological processes through interactions with the neuropeptides orexin A and B. Selective OX1R antagonists exhibit therapeutic effects in preclinical models of several behavioral disorders, including drug seeking and overeating. However, currently there are no selective OX1R antagonists approved for clinical use, fueling demand for novel compounds that act at this target. In this study, we meticulously curated a dataset comprising over 1300 OX1R ligands using a stringent filter and criteria cascade. Subsequently, we developed highly predictive quantitative structure-activity relationship (QSAR) models employing the optimized hyper-parameters for the random forest machine learning algorithm and twelve 2D molecular descriptors selected by recursive feature elimination with a 5-fold cross-validation process. The predictive capacity of the QSAR model was further assessed using an external test set and enrichment study, confirming its high predictivity. The practical applicability of our final QSAR model was demonstrated through virtual screening of the DrugBank database. This revealed two FDA-approved drugs (isavuconazole and cabozantinib) as potential OX1R ligands, confirmed by radiolabeled OX1R binding assays. To our best knowledge, this study represents the first report of highly predictive QSAR models on a large comprehensive dataset of diverse OX1R ligands, which should prove useful for the discovery and design of new compounds targeting this receptor.
    Sprache Englisch
    Erscheinungsdatum 2023-12-20
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article
    ISSN 2949-7477
    ISSN (online) 2949-7477
    DOI 10.1016/j.aichem.2023.100040
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: The sensation seeking trait confers a dormant susceptibility to addiction that is revealed by intermittent cocaine self-administration in rats.

    O'Connor, Shayna L / Aston-Jones, Gary / James, Morgan H

    Neuropharmacology

    2021  Band 195, Seite(n) 108566

    Abstract: Heightened sensation seeking is associated with an increased risk of substance use disorder in clinical populations. In rats, sensation seeking is often examined by measuring locomotor reactivity to a novel environment. So-called high responders (HR) ... ...

    Abstract Heightened sensation seeking is associated with an increased risk of substance use disorder in clinical populations. In rats, sensation seeking is often examined by measuring locomotor reactivity to a novel environment. So-called high responders (HR) acquire self-administration of psychostimulants more quickly and consume higher amounts of drug compared to low responder (LR) rats, indicating that the HR trait might confer a stronger addiction propensity. However, studies of addiction-like behaviors in HR vs LR rats have typically utilized self-administration paradigms that do not dissociate individual differences in the hedonic/reinforcing and motivational properties of a drug. Moreover, little attention has been given to whether HR rats are more susceptible to drug-access conditions that promote a state-dependent addiction phenotype. We report that on a behavioral economics task, HR rats have higher preferred brain-cocaine levels compared to LR rats but do not differ with respect to their demand elasticity for cocaine. In contrast, when tested on an intermittent access schedule of cocaine self-administration, which has been shown to promote several addiction-related endophenotypes, HR rats exhibit greater escalation of intake and more drastic reductions in cocaine demand elasticity. Together, these data indicate that the HR trait does not confer higher extant addiction behavior, but rather that this phenotype is associated with a propensity for addiction that remains dormant until it is actuated by intermittent drug intake. These findings reveal a 'trait' (HR) by 'state' (intermittent drug intake) interaction that produces a strong addiction-like phenotype. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.
    Mesh-Begriff(e) Animals ; Behavior, Animal/drug effects ; Cocaine/administration & dosage ; Cocaine-Related Disorders/physiopathology ; Dopamine Uptake Inhibitors/administration & dosage ; Drug-Seeking Behavior/drug effects ; Male ; Motor Activity/drug effects ; Rats ; Rats, Sprague-Dawley ; Self Administration
    Chemische Substanzen Dopamine Uptake Inhibitors ; Cocaine (I5Y540LHVR)
    Sprache Englisch
    Erscheinungsdatum 2021-04-20
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2021.108566
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Cognitive representations of intracranial self-stimulation of midbrain dopamine neurons depend on stimulation frequency.

    Millard, Samuel J / Hoang, Ivy B / Sherwood, Savannah / Taira, Masakazu / Reyes, Vanessa / Greer, Zara / O'Connor, Shayna L / Wassum, Kate M / James, Morgan H / Barker, David J / Sharpe, Melissa J

    Nature neuroscience

    2024  

    Abstract: Dopamine neurons in the ventral tegmental area support intracranial self-stimulation (ICSS), yet the cognitive representations underlying this phenomenon remain unclear. Here, 20-Hz stimulation of dopamine neurons, which approximates a physiologically ... ...

    Abstract Dopamine neurons in the ventral tegmental area support intracranial self-stimulation (ICSS), yet the cognitive representations underlying this phenomenon remain unclear. Here, 20-Hz stimulation of dopamine neurons, which approximates a physiologically relevant prediction error, was not sufficient to support ICSS beyond a continuously reinforced schedule and did not endow cues with a general or specific value. However, 50-Hz stimulation of dopamine neurons was sufficient to drive robust ICSS and was represented as a specific reward to motivate behavior. The frequency dependence of this effect is due to the rate (not the number) of action potentials produced by dopamine neurons, which differently modulates dopamine release downstream.
    Sprache Englisch
    Erscheinungsdatum 2024-05-13
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1420596-8
    ISSN 1546-1726 ; 1097-6256
    ISSN (online) 1546-1726
    ISSN 1097-6256
    DOI 10.1038/s41593-024-01643-1
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse.

    James, Morgan H / Fragale, Jennifer E / O'Connor, Shayna L / Zimmer, Benjamin A / Aston-Jones, Gary

    Neuropharmacology

    2020  Band 183, Seite(n) 108359

    Abstract: An estimated 50-90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report coabusing alcohol to 'self-medicate' against the negative emotional side effects of the cocaine 'crash', including the onset of anxiety. ... ...

    Abstract An estimated 50-90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report coabusing alcohol to 'self-medicate' against the negative emotional side effects of the cocaine 'crash', including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of cocaine, alcohol, and their combination, as well as reduce the onset of anxiety during drug withdrawal. The hypothalamic orexin (hypocretin) neuropeptide system offers a promising target, as orexin neurons are critically involved in activating behavioral and physiological states to respond to both positive and negative motivators. Here, we seek to describe studies demonstrating efficacy of orexin receptor antagonists in reducing cocaine, alcohol- and stress-related behaviors, but note that these studies have largely focused on each of these phenomena in isolation. For orexin-based compounds to be viable in the clinical setting, we argue that it is imperative that their efficacy be tested in animal models that account for polysubstance use patterns. To begin to examine this, we present new data showing that rats' preferred level of cocaine intake is significantly increased following chronic homecage access to alcohol. We also report that cocaine intake and motivation are reduced by a selective orexin-1 receptor antagonist when rats have a history of cocaine + alcohol, but not a limited history of cocaine alone. In light of these proof-of-principle data, we outline what we believe to be the key priorities going forward with respect to further examining the orexin system in models of polysubstance use. This article is part of the special issue on Neurocircuitry Modulating Drug and Alcohol Abuse.
    Mesh-Begriff(e) Alcoholism/drug therapy ; Alcoholism/metabolism ; Animals ; Anxiety/metabolism ; Cocaine-Related Disorders/drug therapy ; Cocaine-Related Disorders/metabolism ; Humans ; Hypothalamus/metabolism ; Mice ; Models, Animal ; Orexin Receptor Antagonists/therapeutic use ; Orexin Receptors/metabolism ; Orexins/metabolism ; Rats
    Chemische Substanzen Orexin Receptor Antagonists ; Orexin Receptors ; Orexins
    Sprache Englisch
    Erscheinungsdatum 2020-10-19
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2020.108359
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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