Renata C. N. Marchette, Pharm.D., Ph.D.

@article{pmid38128767,

title = {Cold nociception as a measure of hyperalgesia during spontaneous heroin withdrawal in mice},

author = {Lyndsay E Hastings and Emma V Frye and Erika R Carlson and Vicky Chuong and Aniah N Matthews and George F Koob and Leandro F Vendruscolo and Renata C N Marchette},

url = {https://pubmed.ncbi.nlm.nih.gov/38128767/},

doi = {10.1016/j.pbb.2023.173694},

issn = {1873-5177},

year  = {2024},

date = {2024-02-01},

urldate = {2024-02-01},

journal = {Pharmacol Biochem Behav},

volume = {235},

pages = {173694},

abstract = {Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests-thermal gradient ring (5-30 °C, 5-50 °C, 15-40 °C, and 25-50 °C), dynamic cold plate (4 °C to -1 °C at -1 °C/min, -1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)-to measure hyperalgesia in a mouse protocol of heroin dependence. On the thermal gradient ring, mice in the heroin withdrawal group preferred warmer temperatures, and the results depended on the ring's temperature range. On the dynamic cold plate, heroin withdrawal increased the number of nociceptive responses, with a temperature ramp from 4 °C to -1 °C yielding the largest response. On the stable cold plate, heroin withdrawal increased the number of nociceptive responses, and a plate temperature of 2 °C yielded the most significant increase in responses. Among the three tests, the stable cold plate elicited the most robust change in behavior between heroin-dependent and nondependent mice and had the highest throughput. To pharmacologically characterize the stable cold plate test, we used μ-opioid and non-opioid receptor-targeting drugs that have been previously shown to reverse OWIH in mechanical and heat nociception assays. The full μ-opioid receptor agonist methadone and μ-opioid receptor partial agonist buprenorphine decreased OWIH, whereas the preferential μ-opioid receptor antagonist naltrexone increased OWIH. Two N-methyl-d-aspartate receptor antagonists (ketamine, MK-801), a corticotropin-releasing factor 1 receptor antagonist (R121919), a β-adrenergic receptor antagonist (butoxamine), an α-adrenergic receptor agonist (lofexidine), and a 5-hydroxytryptamine-3 receptor antagonist (ondansetron) had no effect on OWIH. These data demonstrate that the stable cold plate at 2 °C yields a robust, reliable, and concise measure of OWIH that is sensitive to opioid agonists.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Leko:2024aa,

title = {Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet},

author = {András H. Lékó and Adriana Gregory-Flores and Renata C. N. Marchette and Juan L. Gomez and Janaina C. M. Vendruscolo and Vez Repunte-Canonigo and Vicky Choung and Sara L. Deschaine and Kimberly E. Whiting and Shelley N. Jackson and Maria Paula Cornejo and Mario Perello and Zhi-Bing You and Michael Eckhaus and Karuna Rasineni and Kim D. Janda and Barry Zorman and Pavel Sumazin and George F. Koob and Michael Michaelides and Pietro P. Sanna and Leandro F. Vendruscolo and Lorenzo Leggio},

url = {https://doi.org/10.1038/s42003-024-06303-5},

doi = {10.1038/s42003-024-06303-5},

isbn = {2399-3642},

year  = {2024},

date = {2024-01-01},

journal = {Communications Biology},

volume = {7},

number = {1},

pages = {632},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37192005,

title = {The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission},

author = {Vicky Chuong and Mehdi Farokhnia and Sophia Khom and Claire L Pince and Sophie K Elvig and Roman Vlkolinsky and Renata Cn Marchette and George F Koob and Marisa Roberto and Leandro F Vendruscolo and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/37192005/},

doi = {10.1172/jci.insight.170671},

issn = {2379-3708},

year  = {2023},

date = {2023-06-01},

urldate = {2023-06-01},

journal = {JCI Insight},

volume = {8},

number = {12},

abstract = {Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36828628,

title = {Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences},

author = {Renata C N Marchette and Erika R Carlson and Emma V Frye and Lyndsay E Hastings and Janaina C M Vendruscolo and Gustavo Mejias-Torres and Stephen J Lewis and Aidan Hampson and Nora D Volkow and Leandro F Vendruscolo and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/36828628/},

doi = {10.1124/jpet.122.001476},

issn = {1521-0103},

year  = {2023},

date = {2023-05-01},

urldate = {2023-05-01},

journal = {J Pharmacol Exp Ther},

volume = {385},

number = {2},

pages = {117--134},

abstract = {The opioid overdose death toll in the United States is an ongoing public health crisis. We characterized the magnitude and duration of respiratory depression, the leading cause of death in opioid overdose cases, induced by heroin or fentanyl and the development of tolerance in male and female rats. We used whole-body plethysmography to first establish dose-response curves by recording breathing for 60 minutes post-intravenous opioid injection. We then tested the development of respiratory tolerance to acute heroin or fentanyl over several weeks and to chronic fentanyl with acute fentanyl or heroin challenge. Heroin and fentanyl each provoked dose-dependent respiratory depression. Heroin caused prolonged (45-60 minute) respiratory depression in female and male rats, characterized by decreased frequency, tidal volume, and minute ventilation and increased inspiratory time and apneic pause. Fentanyl produced similar changes with a shorter duration (10-15 minutes). High-dose heroin or fentanyl produced robust respiratory depression that was slightly more severe in females and, when given intermittently (acute doses 2 to 3 weeks apart), did not lead to tolerance. In contrast, chronic fentanyl delivered with an osmotic minipump resulted in tolerance to acute fentanyl and heroin, characterized by a shorter duration of respiratory depression. This effect persisted during withdrawal in males only. Our model and experimental design will allow for investigation of the neurobiology of opioid-induced respiratory depression and for testing potential therapeutics to reverse respiratory depression or stimulate breathing. SIGNIFICANCE STATEMENT: Fentanyl was more potent and had shorter duration in producing respiratory depression than heroin in both sexes, whereas female rats were more sensitive than males to heroin-induced respiratory depression. Tolerance/cross-tolerance develops in chronic fentanyl administration but is minimized with long interadministration intervals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36683829b,

title = {Extended access to fentanyl vapor self-administration leads to addiction-like behaviors in mice: Blood chemokine/cytokine levels as potential biomarkers},

author = {Renata C N Marchette and Erika R Carlson and Nadia Said and George F Koob and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/36683829/},

doi = {10.1016/j.addicn.2022.100057},

issn = {2772-3925},

year  = {2023},

date = {2023-03-01},

urldate = {2023-03-01},

journal = {Addict Neurosci},

volume = {5},

abstract = {Rodent models are useful for understanding the mechanisms that underlie opioid addiction, but most preclinical studies have focused on rewarding and consummatory aspects of opioids without components of dependence-induced escalation of drug taking or seeking. We characterized several opioid-related behaviors in mice using a model of vaporized fentanyl self-administration. Male and female C57BL/6J mice were assigned to short-access (ShA; 1 h, nondependent) or long-access (LgA; 6 h, dependent) fentanyl vapor self-administration and subsequently tested in a battery of behavioral tests, followed by blood collection during withdrawal. Compared with mice in the ShA group, mice in the LgA group escalated their fentanyl intake, were more motivated to work to obtain the drug, exhibited greater hyperalgesia, and exhibited greater signs of naloxone-precipitated withdrawal. Principal component analysis indicated the emergence of two independent behavioral constructs: "intake/motivation" and "hyperalgesia/punished seeking." In mice in the LgA condition only, "hyperalgesia/punished seeking" was associated with plasma levels of proinflammatory interleukin-17 (IL-17), chemokine (C-C motif) ligand 4 (CCL-4), and tumor necrosis factor  (TNF-). Overall, the results suggest that extended access to opioids leads to addiction-like behavior, and some constructs that are associated with addiction-like behavior may be associated with levels of the proinflammatory cytokines/chemokines IL-17, TNF-, and CCL-4 in blood.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36123420b,

title = {Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies},

author = {Mehdi Farokhnia and Christopher T Rentsch and Vicky Chuong and M Adrienne McGinn and Sophie K Elvig and Eliza A Douglass and Luis A Gonzalez and Jenna E Sanfilippo and Renata C N Marchette and Brendan J Tunstall and David A Fiellin and George F Koob and Amy C Justice and Lorenzo Leggio and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/36123420/},

doi = {10.1038/s41380-022-01736-y},

issn = {1476-5578},

year  = {2022},

date = {2022-11-01},

urldate = {2022-11-01},

journal = {Mol Psychiatry},

volume = {27},

number = {11},

pages = {4642--4652},

abstract = {Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33997152,

title = {κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats},

author = {Renata C N Marchette and Adriana Gregory-Flores and Brendan J Tunstall and Erika R Carlson and Shelley N Jackson and Agnieszka Sulima and Kenner C Rice and George F Koob and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/33997152/},

doi = {10.1016/j.ynstr.2021.100325},

issn = {2352-2895},

year  = {2021},

date = {2021-05-01},

urldate = {2021-05-01},

journal = {Neurobiol Stress},

volume = {14},

pages = {100325},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Moussawi:2020aa,

title = {Fentanyl vapor self-administration model in mice to study opioid addiction.},

author = {K Moussawi and M M Ortiz and S C Gantz and B J Tunstall and R C N Marchette and A Bonci and G F Koob and L F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/32821843/},

doi = {10.1126/sciadv.abc0413},

year  = {2020},

date = {2020-08-01},

urldate = {2020-08-01},

journal = {Sci Adv},

volume = {6},

number = {32},

pages = {eabc0413},

abstract = {Intravenous drug self-administration is considered the "gold standard" model to investigate the neurobiology of drug addiction in rodents. However, its use in mice is limited by frequent complications of intravenous catheterization. Given the many advantages of using mice in biomedical research, we developed a noninvasive mouse model of opioid self-administration using vaporized fentanyl. Mice readily self-administered fentanyl vapor, titrated their drug intake, and exhibited addiction-like behaviors, including escalation of drug intake, somatic signs of withdrawal, drug intake despite punishment, and reinstatement of drug seeking. Electrophysiological recordings from ventral tegmental area dopamine neurons showed a lower amplitude of GABA(B) receptor-dependent currents during protracted abstinence from fentanyl vapor self-administration. This mouse model of fentanyl self-administration recapitulates key features of opioid addiction, overcomes limitations of the intravenous model, and allows investigation of the neurobiology of opioid addiction in unprecedented ways.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}