2025 |
Grodin, Erica N; Karoly, Hollis; Browning, Brittney D; Coleman, Leon; Farokhnia, Mehdi; Kryszak, Lindsay A; Meredith, Lindsay R; Squeglia, Lindsay M In: Neurosci Biobehav Rev, vol. 173, pp. 106142, 2025, ISSN: 1873-7528. @article{pmid40216171,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. |
Richardson, Rani S; Kryszak, Lindsay A; Vendruscolo, Janaina C M; Koob, George F; Vendruscolo, Leandro F; Leggio, Lorenzo In: Mol Psychiatry, vol. 30, no. 3, pp. 1047–1056, 2025, ISSN: 1476-5578. @article{pmid39232198b,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. |
Richardson, Rani S; Kryszak, Lindsay A; Vendruscolo, Janaina C M; Koob, George F; Leggio, Lorenzo; Vendruscolo, Leandro F Evidence for independent actions of the CRF and ghrelin systems in binge-like alcohol drinking in mice Journal Article In: Prog Neuropsychopharmacol Biol Psychiatry, vol. 138, pp. 111341, 2025, ISSN: 1878-4216. @article{pmid40139339,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. |
2024 |
Bossert, Jennifer M; Caldwell, Kiera E; Korah, Hannah; Batista, Ashley; Bonbrest, Hannah; Fredriksson, Ida; Jackson, Shelley N; Sulima, Agnieszka; Rice, Kenner C; Zaveri, Nurulain T; Shaham, Yavin In: Psychopharmacology (Berl), vol. 241, no. 12, pp. 2497–2511, 2024, ISSN: 1432-2072. @article{pmid39269500,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. |
Lékó, András H; Gregory-Flores, Adriana; Marchette, Renata C N; Gomez, Juan L; Vendruscolo, Janaina C M; Repunte-Canonigo, Vez; Choung, Vicky; Deschaine, Sara L; Whiting, Kimberly E; Jackson, Shelley N; Cornejo, Maria Paula; Perello, Mario; You, Zhi-Bing; Eckhaus, Michael; Rasineni, Karuna; Janda, Kim D; Zorman, Barry; Sumazin, Pavel; Koob, George F; Michaelides, Michael; Sanna, Pietro P; Vendruscolo, Leandro F; Leggio, Lorenzo Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet Journal Article In: Commun Biol, vol. 7, no. 1, pp. 632, 2024, ISSN: 2399-3642. @article{pmid38796563b,The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity. |
2021 |
Marchette, Renata C N; Gregory-Flores, Adriana; Tunstall, Brendan J; Carlson, Erika R; Jackson, Shelley N; Sulima, Agnieszka; Rice, Kenner C; Koob, George F; Vendruscolo, Leandro F κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats Journal Article In: Neurobiol Stress, vol. 14, pp. 100325, 2021, ISSN: 2352-2895. @article{pmid33997152,Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hyperalgesia remains to be determined. We hypothesized that KOR antagonism would reverse opioid withdrawal-induced hyperalgesia in opioid-dependent rats. Male and female Wistar rats received daily injections of heroin (2-6 mg/kg, SC) and were tested for mechanical sensitivity in the electronic von Frey test 4-6 h into withdrawal. Female rats required significantly more heroin than male rats to reach comparable levels of both heroin-induced analgesia and hyperalgesia (6 mg/kg 2 mg/kg). Once hyperalgesia was established, we tested the effects of the KOR antagonists nor-binaltorphimine (norBNI; 30 mg/kg, SC) and 5'-guanidinonaltrindole (5'GNTI; 30 mg/kg, SC). When the animals continued to receive their daily heroin treatment (or saline treatment in the repeated saline group) five times per week throughout the experiment, both KOR antagonists reversed heroin withdrawal-induced hyperalgesia. The anti-hyperalgesia effect of norBNI was more prolonged in males than in females (14 days 7 days), whereas 5'GNTI had more prolonged effects in females than in males (14 days 4 days). The behavioral effects of 5'GNTI coincided with higher 5'GNTI levels in the brain than in plasma when measured at 24 h, whereas 5'GNTI did not reverse hyperalgesia at 30 min posttreatment when 5'GNTI levels were higher in plasma than in the brain. Finally, we tested the effects of 5'GNTI on naloxone-induced and spontaneous signs of opioid withdrawal and found no effect in either male or female rats. These findings indicate a functional role for KORs in heroin withdrawal-induced hyperalgesia that is observed in rats of both sexes. |
Kärkkäinen, Olli; Farokhnia, Mehdi; Klåvus, Anton; Auriola, Seppo; Lehtonen, Marko; Deschaine, Sara L; Piacentino, Daria; Abshire, Kelly M; Jackson, Shelley N; Leggio, Lorenzo In: Alcohol Clin Exp Res, vol. 45, no. 11, pp. 2207–2216, 2021, ISSN: 1530-0277. @article{pmid34590334,BACKGROUND: Ghrelin may influence several alcohol-related behaviors in animals and humans by modulating central and/or peripheral biological pathways. The aim of this exploratory analysis was to investigate associations between ghrelin administration and the human circulating metabolome during alcohol exposure in nontreatment seeking, heavy drinking individuals with alcohol use disorder (AUD). METHODS: We used serum samples from a randomized, crossover, double-blind, placebo-controlled human laboratory study with intravenous (IV) ghrelin or placebo infusion in two experiments. During each session, participants received a loading dose (3 µg/kg) followed by continuous infusion (16.9 ng/kg/min) of acyl ghrelin or placebo. The first experiment included an IV alcohol self-administration (IV-ASA) session and the second experiment included an IV alcohol clamp (IV-AC) session, both with the counterbalanced infusion of ghrelin or placebo. Serum metabolite profiles were analyzed from repeated blood samples collected during each session. RESULTS: In both experiments, ghrelin infusion was associated with an altered serum metabolite profile, including significantly increased levels of cortisol (IV-ASA q-value = 0.0003 and IV-AC q < 0.0001), corticosterone (IV-ASA q = 0.0202 and IV-AC q < 0.0001), and glycochenodeoxycholic acid (IV-ASA q = 0.0375 and IV-AC q = 0.0013). In the IV-ASA experiment, ghrelin infusion increased levels of cortisone (q = 0.0352) and fatty acids 18:1 (q = 0.0406) and 18:3 (q = 0.0320). Moreover, in the IV-AC experiment, ghrelin infusion significantly increased levels of glycocholic acid (q < 0.0001) and phenylalanine (q = 0.0458). CONCLUSION: IV ghrelin infusion, combined with IV alcohol administration, was associated with increases in the circulating metabolite levels of corticosteroids and glycine-conjugated bile acids, among other changes. Further research is needed to understand the role that metabolomic changes play in the complex interaction between ghrelin and alcohol. |
Translational Analytical Core – Publications
2025 |
In: Neurosci Biobehav Rev, vol. 173, pp. 106142, 2025, ISSN: 1873-7528. |
In: Mol Psychiatry, vol. 30, no. 3, pp. 1047–1056, 2025, ISSN: 1476-5578. |
Evidence for independent actions of the CRF and ghrelin systems in binge-like alcohol drinking in mice Journal Article In: Prog Neuropsychopharmacol Biol Psychiatry, vol. 138, pp. 111341, 2025, ISSN: 1878-4216. |
2024 |
In: Psychopharmacology (Berl), vol. 241, no. 12, pp. 2497–2511, 2024, ISSN: 1432-2072. |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet Journal Article In: Commun Biol, vol. 7, no. 1, pp. 632, 2024, ISSN: 2399-3642. |
2021 |
κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats Journal Article In: Neurobiol Stress, vol. 14, pp. 100325, 2021, ISSN: 2352-2895. |
In: Alcohol Clin Exp Res, vol. 45, no. 11, pp. 2207–2216, 2021, ISSN: 1530-0277. |
