Translational Analytical Core – Publications

@article{pmid42392315,

title = {Leveraging barbershops for community-based addiction research: A pilot study using hair samples to detect fentanyl and stress biomarkers},

author = {Nicholaus J Christian and Lisa A Farinelli and Meg Jordan and Shelley N Jackson and Lindsay A Kryszak and Garrick Sherman and Stephanie T Weiss and Stephen B Thomas and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/42392315/},

doi = {10.1016/j.josat.2026.210063},

issn = {2949-8759},

year  = {2026},

date = {2026-11-01},

urldate = {2026-11-01},

journal = {J Subst Use Addict Treat},

volume = {190},

pages = {210063},

abstract = {INTRODUCTION: The ongoing opioid overdose crisis disproportionately affects minority communities, highlighting the urgent need for community-based addiction research to better understand and address this public health issue. Community-academic partnerships are a key strategy to engage these communities in addiction research. Here we describe the Health Advocates In-Reach and Research (HAIR) initiative, a collaboration between the University of Maryland and the National Institute on Drug Abuse Intramural Research Program. We tested whether barbershops, a trusted community venue, can support hair collection for fentanyl toxicology and a stress biomarker (cortisol) to inform equitable overdose prevention.nnMETHODS: Within the HAIR initiative, community barbers/stylists and academic partners co-designed an anonymized, barbershop-based hair collection pilot project. Prespecified objectives were to (1) build trust between researchers and community members, (2) evaluate feasibility (successful collection and laboratory assay completion) and acceptability, (3) quantify fentanyl in hair, (4) quantify hair cortisol, and (5) explore associations between fentanyl detection and cortisol. Liquid chromatography-mass spectrometry (LC/MS) assays for quantitative analysis were developed and applied. Forty samples were collected from predominantly Black (85%), non-Hispanic (77.5%), male (95%) patrons.nnRESULTS: Cortisol concentrations were successfully measured in 36 of the 40 samples, ranging from 3.36 to 104.00 pg/mg. Fentanyl was detected in 13 of the 40 samples, specifically four in quantifiable amounts (10.20-171.00 pg/mg) and nine samples containing trace amounts below the limit of quantification. An ordinary least squares regression model suggested that fentanyl presence may be predictive of increased cortisol after controlling for demographic variables. This association did not reach statistical significance (p = .065), likely due to limited statistical power from the small sample size.nnCONCLUSIONS: This pilot study presents a promising community-based translational research model to advance addiction implementation science. Barbershops represent a feasible, acceptable setting for community-based hair toxicology and stress biomarker collection, enabling the identification of otherwise unrecognized exposure and stress signals within high-burden populations. This practice-ready workflow could augment local overdose strategies, linking on-site findings to naloxone distribution and rapid Medications for Opioid Use Disorder (MOUD) navigation, and merits evaluation in larger hybrid implementation science studies.},

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pubstate = {published},

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}

@article{pmid42090839,

title = {GHSR antagonist LEAP2 concentrations negatively correlate with alcohol craving and are modulated by alcohol exposure: Evidence from human and rat studies},

author = {Andras H Leko and Mehdi Farokhnia and Elizabeth H Tressler and Janaina C M Vendruscolo and Lindsay A Kryszak and Shelley N Jackson and Lisa A Farinelli and Olivia Jennings and Zhihong Yang and Carolina L Haass-Koffler and Leandro F Vendruscolo and Suthat Liangpunsakul and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/42090839/},

doi = {10.1016/j.drugalcdep.2026.113176},

issn = {1879-0046},

year  = {2026},

date = {2026-07-01},

urldate = {2026-07-01},

journal = {Drug Alcohol Depend},

volume = {284},

pages = {113176},

abstract = {BACKGROUND: Despite its clinical significance, pharmacological treatment options for alcohol use disorder (AUD) remained limited, which highlights the need for novel therapeutic targets. The ghrelin system has emerged as an important regulator of alcohol craving and intake. Liver-expressed antimicrobial peptide 2 (LEAP2) has recently been identified as an endogenous ghrelin receptor (GHSR) antagonist that influences metabolic and reward-related pathways.nnMETHODS: As a secondary analysis of five different clinical trials, we measured LEAP2 concentrations in the collected blood samples and examined their association with alcohol craving and the effects of both acute and chronic alcohol use on LEAP2. In addition, we complemented these clinical trial analyses by conducting preclinical experiments in wild-type and GHSR-KO Wistar rats to investigate the effects of alcohol and ghrelin on LEAP2 concentrations.nnRESULTS: In humans, LEAP2 concentrations negatively correlated with both priming- and cue-induced alcohol craving. Acute alcohol administration reduced LEAP2 concentrations 90min after oral alcohol intake, a response that was attenuated by co-administration of the GHSR inverse agonist PF-5190457. An intraperitoneal alcohol administration after a pre-treatment with ghrelin reduced LEAP2 concentrations in wild-type but not GHSR-KO Wistar rats. In contrast to acute alcohol administration, LEAP2 concentrations did not differ between people with alcohol use disorder and healthy controls and were unaffected by evidence of hepatocyte injury and alcohol abstinence.nnCONCLUSIONS: These results enhance our understanding of the ghrelin system, particularly LEAP2, with regard to alcohol craving and consumption. This work may inform the development of novel interventions for alcohol use disorder.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid42505410,

title = {Orforglipron, a Small-Molecule Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA), Has Neuroprotective and Anti-Inflammatory Effects},

author = {Yazhou Li and Elliot J Glotfelty and Pathik Parekh and Buyandelger Batsaikhan and Weiming Luo and Shelley N Jackson and Brandon K Harvey and Nigel H Greig},

url = {https://pubmed.ncbi.nlm.nih.gov/42505410/},

doi = {10.3390/cells15141301},

issn = {2073-4409},

year  = {2026},

date = {2026-07-01},

urldate = {2026-07-01},

journal = {Cells},

volume = {15},

number = {14},

abstract = {GLP-1 receptor (GLP-1R) agonists, widely used for diabetes and obesity management, have shown preclinical and clinical promise as potential therapeutics for neurological conditions. Until 2026, all U.S. Food and Drug Administration (FDA)-approved GLP-1 drugs were peptide-based, with most requiring daily or weekly subcutaneous injections. Despite their large size and low brain penetrance, several peptide-based GLP-1 drugs are in clinical trials for neurologic indications. Recently, the FDA approved orforglipron as the first small-molecule, non-peptide, orally bioavailable human GLP-1 receptor agonist, and it may offer advantages over peptide-based counterparts. We hence evaluated whether it possesses similar neurotrophic, neuroprotective, and anti-inflammatory attributes. Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties. Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries. Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line. Actions were replicated under insulin resistance-a potential cause of neurodegenerative conditions-in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism. Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs. Nevertheless, orforglipron may provide potential value in specific neurological conditions.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid41632547,

title = {Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone},

author = {Emma V Frye and Lyndsay E Hastings and Aniah N Matthews and Adriana Gregory-Flores and Janaina Cm Vendruscolo and Lindsay A Kryszak and Shelley N Jackson and Aidan J Hampson and Nora D Volkow and Leandro F Vendruscolo and Renata Cn Marchette and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/41632547/},

doi = {10.1172/jci.insight.198059},

issn = {2379-3708},

year  = {2026},

date = {2026-03-01},

urldate = {2026-03-01},

journal = {JCI Insight},

volume = {11},

number = {6},

abstract = {The high frequency of opioid overdose deaths often involves co-use of alcohol, which is reported in approximately 30% of fentanyl fatalities. Both substances depress respiratory function, and their combined effects can be lethal. The present study investigated physiological parameters of respiratory-depressant effects of fentanyl when coadministered with alcohol and their sensitivity to naloxone reversal using whole-body plethysmography in male and female Long-Evans rats. Administration of a high, sedative-like dose of alcohol alone or fentanyl alone resulted in no mortality, but fentanyl plus alcohol led to mortality rates of 42% and 33% in females and males, respectively. The fentanyl+alcohol combination reduced minute ventilation and increased apneic pauses compared with either drug alone. Lower, binge-like alcohol doses when combined with fentanyl also amplified respiratory depression. Pretreatment with naloxone did not fully restore normal respiration. Naloxone administered after fentanyl+alcohol transiently reversed the decrease in minute ventilation but did not reverse apneic pauses. Fentanyl-dependent rats were partially tolerant to fentanyl- and fentanyl+alcohol-induced respiratory depression, but alcohol-dependent rats exhibited sensitization to alcohol- and fentanyl+alcohol-induced apnea. These findings highlight physiological parameters of severe respiratory risks with fentanyl+alcohol co-use, which are inadequately reversed by naloxone, underscoring the need for targeted strategies to manage opioid+alcohol overdoses.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid41193673,

title = {The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects},

author = {Dino Luethi and Grant C Glatfelter and Eline Pottie and Francesca Sellitti and Alexander D Maitland and Nicholas R Gonzalez and Lindsay A Kryszak and Shelley N Jackson and Marius C Hoener and Christophe P Stove and Matthias E Liechti and Martin Smieško and Michael H Baumann and Linda D Simmler and Deborah Rudin},

url = {https://pubmed.ncbi.nlm.nih.gov/41193673/},

doi = {10.1038/s41380-025-03325-1},

issn = {1476-5578},

year  = {2026},

date = {2026-03-01},

urldate = {2026-03-01},

journal = {Mol Psychiatry},

volume = {31},

number = {3},

pages = {1799--1809},

abstract = {Various ring-substituted α-methylphenethylamines (i.e., amphetamines) produce psychedelic-like effects that are primarily mediated by activity at 5-hydroxytryptamine 2A (5-HT) receptors. Small lipophilic substituents at the 4-position of the 2,5-dimethoxyamphetamine core structure can greatly enhance the clinical potency of such derivatives. Here, we studied the effects of various 4-alkylated 2,5-dimethoxyamphetamines (4-methyl, 4-ethyl, 4-propyl, 4-butyl, 4-amyl) on in vitro receptor activities and in vivo psychedelic-like effects in mice. The acute effects of the compounds were examined using the mouse head-twitch response (HTR) assay, a proxy for psychedelic-like drug actions. Overall, the series primarily interacted with 5-HT receptor subtypes, with increasing 4-alkyl chain length associated with increased affinity at 5-HT receptors. For all three in vitro functional readouts assessed, the 4-propyl analog produced the highest potencies for 5-HT receptor activation (1-9 nM), but smaller and longer chain lengths displayed comparable activities (2-56 nM). In mice, the compounds displayed variable maximal HTR counts (23-119) and potencies (0.42-2.76 mg/kg), with the 4-propyl and 4-methyl compounds being the most potent and efficacious, respectively. Analysis of drug concentrations in mouse plasma, brain tissue, and brain dialysate samples revealed that derivatives with longer alkyl chains (i.e., butyl, amyl) require higher systemic doses to achieve concentrations comparable to those of short-chain analogs. These findings demonstrate that extending the 4-position alkyl chain beyond a propyl group reduces in vivo potency and efficacy, in part due to pharmacokinetic parameters.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid40523512b,

title = {Locomotor activity depends on β-arrestin recruitment by the dopamine D receptor in the striatal D-D receptor heteromer},

author = {Alexandra H Evans and Marc Ciruela-Jardí and William Rea and Bradley M Keegan and Marjorie R Levinstein and Alessandro Bonifazi and Jianjing Cao and Shelley N Jackson and Lei Shi and Nil Casajuana-Martin and Ning-Sheng Cai and Vicent Casadó and Christopher J Earley and Amy H Newman and Michael Michaelides and Leonardo Pardo and Estefanía Moreno and Sergi Ferré},

url = {https://pubmed.ncbi.nlm.nih.gov/40523512/},

doi = {10.1016/j.phrs.2025.107826},

issn = {1096-1186},

year  = {2025},

date = {2025-08-01},

urldate = {2025-08-01},

journal = {Pharmacol Res},

volume = {218},

pages = {107826},

abstract = {Several dopaminergic compounds, including the clinically used pramipexole, are labelled as preferential dopamine D receptor (DR) agonists based on their moderately higher affinity for the DR versus other D-like receptor subtypes. In rodents, these compounds typically produce locomotor depression with low doses and locomotor activation with higher doses, which has been assumed to be mediated by presynaptic DRs and postsynaptic striatal DRs, respectively. However, studies with selective pharmacological and genetic blockade of each dopamine receptor subtype suggest opposite roles. We address this apparent conundrum by performing a comprehensive in vitro, in vivo and ex vivo pharmacological comparison of several preferential DR agonists. Their differential properties reveal that their locomotor activating effects in mice are dependent on the striatal postsynaptic DRs forming heteromers with DRs, via their ability to potentiate β-arrestin recruitment by the DR in the DR-DR heteromer. The results also indicate that the locomotor depressant effects are largely dependent on their ability to activate presynaptic DRs. More broadly, it is demonstrated that locomotor activity in mice depends on β-arrestin recruitment by the DR in the striatal DR-DR heteromer. These results can have implications for the treatment of L-dopa-induced dyskinesia and Restless Legs Syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40216171,

title = {Utilizing blood inflammatory markers in alcohol studies: Considerations and recommendations for study design, sample collection, and data analysis},

author = {Erica N Grodin and Hollis Karoly and Brittney D Browning and Leon Coleman and Mehdi Farokhnia and Lindsay A Kryszak and Lindsay R Meredith and Lindsay M Squeglia},

url = {https://pubmed.ncbi.nlm.nih.gov/40216171/},

doi = {10.1016/j.neubiorev.2025.106142},

issn = {1873-7528},

year  = {2025},

date = {2025-04-01},

urldate = {2025-04-01},

journal = {Neurosci Biobehav Rev},

volume = {173},

pages = {106142},

abstract = {A large body of evidence suggests that heavy alcohol use is associated with dysregulated immune function, and that immune dysfunction in turn contributes to the pathophysiology of alcohol use disorder (AUD). As such, alcohol researchers have increasingly begun to include measurements of immune function-primarily peripheral circulating cytokines-in human studies, with the goal of testing associations with clinically-relevant behavioral measures. To date, findings and implications from these studies have been inconsistent and difficult to interpret, likely due to methodological challenges related to study design and implementation. In particular, the existing literature has demonstrated sample processing concerns, differences in assay methods, limited selection of analytes, and sample selection biases, all of which may contribute to inconsistent results. We briefly review the field, discuss these and other challenges, and propose guidance for designing studies on inflammation among heavy-drinking human participants. We note that conducting such studies requires appreciable consideration and planning, and ideally should involve an interdisciplinary team of experts, including immunologists, physiologists, and technical experts in bioassays, alongside experts in the field of interest (e.g., AUD). We highlight the importance of considering participant selection, analyte selection, sample collection, sample handling and storage, and assay methods, and suggest that the field move towards standardization of procedures and reporting. We propose that undertaking these changes in study design and implementation should produce consilience in findings and aid in our overall understanding of the complex relationship between alcohol exposure and immune function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39232198b,

title = {GHSR blockade, but not reduction of peripherally circulating ghrelin via β-adrenergic receptor antagonism, decreases binge-like alcohol drinking in mice},

author = {Rani S Richardson and Lindsay A Kryszak and Janaina C M Vendruscolo and George F Koob and Leandro F Vendruscolo and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/39232198/},

doi = {10.1038/s41380-024-02713-3},

issn = {1476-5578},

year  = {2025},

date = {2025-03-01},

urldate = {2025-03-01},

journal = {Mol Psychiatry},

volume = {30},

number = {3},

pages = {1047--1056},

abstract = {Alcohol use disorder (AUD) and binge drinking are highly prevalent public health issues. The stomach-derived peptide ghrelin, and its receptor, the growth hormone secretagogue receptor (GHSR), both of which are expressed in the brain and periphery, are implicated in alcohol-related outcomes. We previously found that systemic and central administration of GHSR antagonists reduced binge-like alcohol drinking, whereas a ghrelin vaccine did not. Thus, we hypothesized that central GHSR drives binge-like alcohol drinking independently of peripheral ghrelin. To investigate this hypothesis, we antagonized β-adrenergic receptors (βARs), which are required for peripheral ghrelin release, and combined them with GHSR blockers. We found that both systemic βAR antagonism with atenolol (peripherally restricted) and metoprolol (brain permeable) robustly decreased plasma ghrelin levels. Also, ICV administration of atenolol had no effect on peripheral endogenous ghrelin levels. However, only metoprolol, but not atenolol, decreased binge-like alcohol drinking. The βAR antagonism also did not prevent the effects of the GHSR blockers JMV2959 and PF-5190457 in decreasing binge-like alcohol drinking. These results suggest that the GHSR rather than peripheral endogenous ghrelin is involved in binge-like alcohol drinking. Thus, GHSRs and βARs represent possible targets for therapeutic intervention for AUD, including the potential combination of drugs that target these two systems.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40139339,

title = {Evidence for independent actions of the CRF and ghrelin systems in binge-like alcohol drinking in mice},

author = {Rani S Richardson and Lindsay A Kryszak and Janaina C M Vendruscolo and George F Koob and Lorenzo Leggio and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/40139339/},

doi = {10.1016/j.pnpbp.2025.111341},

issn = {1878-4216},

year  = {2025},

date = {2025-03-01},

urldate = {2025-03-01},

journal = {Prog Neuropsychopharmacol Biol Psychiatry},

volume = {138},

pages = {111341},

abstract = {Alcohol use disorder (AUD) and binge drinking are highly prevalent public health issues. Both ghrelin and corticotrophin-releasing factor (CRF) drive stress responses and alcohol drinking. Despite evidence of a relationship between the ghrelin and CRF systems, their potential interaction in modulating alcohol drinking is unclear. We tested the effect of a brain-penetrant CRF receptor antagonist (R121919) and a peripherally restricted nonselective CRF receptor antagonist (astressin) on plasma ghrelin levels. We also tested effects of R121919 and astressin alone and combined with the growth hormone secretagogue receptor (GHSR; the ghrelin receptor) antagonist JMV2959 and GHSR antagonist/inverse agonist PF-5190457 in a model of binge-like alcohol drinking in male and female C57BL/6 J mice. The intraperitoneal administration of R121919 but not astressin increased plasma ghrelin levels. R121919 but not astressin reduced binge-like alcohol drinking. CRF receptor antagonism had no effect on the ability of GHSR blockers to reduce alcohol drinking. No sex × drug treatment interactions were observed. These findings suggest that while both CRF receptor antagonism and GHSR antagonism reduce alcohol drinking, these two pharmacological approaches may not interact to mediate binge-like alcohol drinking in mice. Additionally, these results provide evidence that GHSR but not peripheral endogenous ghrelin may be key in driving binge-like alcohol drinking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39269500,

title = {Effect of chronic delivery of the NOP/MOR partial agonist AT-201 and NOP antagonist J-113397 on heroin relapse in a rat model of opioid maintenance},

author = {Jennifer M Bossert and Kiera E Caldwell and Hannah Korah and Ashley Batista and Hannah Bonbrest and Ida Fredriksson and Shelley N Jackson and Agnieszka Sulima and Kenner C Rice and Nurulain T Zaveri and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/38796563/},

doi = {10.1007/s00213-024-06678-7},

issn = {1432-2072},

year  = {2024},

date = {2024-12-01},

urldate = {2024-12-01},

journal = {Psychopharmacology (Berl)},

volume = {241},

number = {12},

pages = {2497--2511},

abstract = {RATIONALE: The opioid crisis persists despite availability of effective opioid agonist maintenance treatments (methadone and buprenorphine). Thus, there is a need to advance novel medications for the treatment of opioid use and relapse.nnOBJECTIVES: We recently modeled maintenance treatment in rats and found that chronic delivery of buprenorphine and the mu opioid receptor (MOR) partial agonist TRV130 decreases relapse to oxycodone seeking and taking. In contrast, chronic delivery of the buprenorphine analog BU08028 had mixed effects on different heroin relapse-related measures. Here, we tested the effect of the mixed nociceptin (NOP) receptor/MOR partial agonist AT-201 and the NOP receptor antagonist J-113397 on different heroin relapse-related measures.nnMETHODS: We trained male and female rats to self-administer heroin (6-h/d, 14-d) in context A and then implanted osmotic minipumps containing AT-201 (0, 3.8, or 12 mg/kg/d) or J-113397 (0, 12.6, or 40 mg/kg/d). Next, we tested the effect of chronic delivery of the compounds on (1) incubation of heroin seeking in a non-drug context B, (2) extinction responding reinforced by heroin-associated discrete cues in context B, (3) context A-induced reinstatement of heroin seeking, and (4) reacquisition of heroin self-administration in context A.nnRESULTS: In females, AT-201 modestly increased reacquisition of heroin self-administration and J-113397 modestly decreased incubation of heroin seeking. The compounds had no effect on the other relapse-related measures in females, and no effect on any of the measures in males.nnCONCLUSION: The NOP/MOR partial agonist AT-201 and the NOP antagonist J-113397 did not mimic buprenorphine's inhibitory effects on relapse in a rat model of opioid maintenance treatment.},

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}