Contact
Biomedical Research Center251 Bayview Blvd.
Suite 200
Room 08A727
Baltimore, MD 21224
Phone: 443-740-2869
Email: leandro.vendruscolo@nih.gov
Education
Ph.D., Pharmacology – Department of Pharmacology, Federal University of Santa Catarina – Brazil
M.S., Pharmacology – Department of Pharmacology, Federal University of Santa Catarina – Brazil
Pharm.D. – Health Sciences Center, Federal University of Santa Catarina – Brazil
Research Interests
The research interest of the Stress & Addiction Neuroscience Unit (SANU) involves investigations of the neurobiology that underlies drug- and stress-related behaviors using preclinical models from a translational perspective. Dr. Vendruscolo began his research career in 1999 while he was in Pharmacy School at the Federal University of Santa Catarina, Brazil, investigating interactions between a psychostimulant and stress. He followed up with M.S. and Ph.D. degrees in pharmacology at the Federal University of Santa Catarina, Brazil, and University of Bordeaux, France, in which he investigated the influence of sex, genetic background, and environment on stress- and drug-related behaviors. During his postdoctoral training, he found that reward overactivation during adolescence in rats had enduring effects on reward function later in life, consistent with a depression-like phenotype. Moreover, he discovered a critical contribution of corticoids and their receptors on addiction-like behaviors and that the blockade of glucocorticoid receptors or mineralocorticoid receptors decreased alcohol drinking and craving in people with alcohol use disorder. Dr. Vendruscolo has been developing new models of drug addiction and investigating the neurobiology of enhanced drug taking and seeking based on the concept that these maladaptive behaviors involve neurotransmitter imbalance in brain regions that are involved in reward, stress, and executive function.
Publications
Selected Publications
2024
Nisbett, Khalin E; Vendruscolo, Leandro F; Koob, George F
µ-Opioid receptor antagonism facilitates the anxiolytic-like effect of oxytocin in mice Journal Article
In: Transl Psychiatry, vol. 14, no. 1, pp. 125, 2024, ISSN: 2158-3188.
@article{pmid38413576,
title = {µ-Opioid receptor antagonism facilitates the anxiolytic-like effect of oxytocin in mice},
author = {Khalin E Nisbett and Leandro F Vendruscolo and George F Koob},
url = {https://pubmed.ncbi.nlm.nih.gov/38413576/},
doi = {10.1038/s41398-024-02830-1},
issn = {2158-3188},
year = {2024},
date = {2024-02-01},
urldate = {2024-02-01},
journal = {Transl Psychiatry},
volume = {14},
number = {1},
pages = {125},
abstract = {Mood and anxiety disorders are leading causes of disability worldwide and are major contributors to the global burden of diseases. Neuropeptides, such as oxytocin and opioid peptides, are important for emotion regulation. Previous studies have demonstrated that oxytocin reduced depression- and anxiety-like behavior in male and female mice, and opioid receptor activation reduced depression-like behavior. However, it remains unclear whether the endogenous opioid system interacts with the oxytocin system to facilitate emotion regulation in male and female mice. We hypothesized that opioid receptor blockade would inhibit the anxiolytic- and antidepressant-like effects of oxytocin. In this study, we systemically administered naloxone, a preferential μ-opioid receptor antagonist, and then intracerebroventricularly administered oxytocin. We then tested mice on the elevated zero maze and the tail suspension tests, respective tests of anxiety- and depression-like behavior. Contrary to our initial hypothesis, naloxone potentiated the anxiolytic-like, but not the antidepressant-like, effect of oxytocin. Using a selective μ-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, and a selective κ-opioid receptor antagonist, norbinaltorphimine, we demonstrate that μ-opioid receptor blockade potentiated the anxiolytic-like effect of oxytocin, whereas κ-opioid receptor blockade inhibited the oxytocin-induced anxiolytic-like effects. The present results suggest that endogenous opioids can regulate the oxytocin system to modulate anxiety-like behavior. Potential clinical implications of these findings are discussed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mood and anxiety disorders are leading causes of disability worldwide and are major contributors to the global burden of diseases. Neuropeptides, such as oxytocin and opioid peptides, are important for emotion regulation. Previous studies have demonstrated that oxytocin reduced depression- and anxiety-like behavior in male and female mice, and opioid receptor activation reduced depression-like behavior. However, it remains unclear whether the endogenous opioid system interacts with the oxytocin system to facilitate emotion regulation in male and female mice. We hypothesized that opioid receptor blockade would inhibit the anxiolytic- and antidepressant-like effects of oxytocin. In this study, we systemically administered naloxone, a preferential μ-opioid receptor antagonist, and then intracerebroventricularly administered oxytocin. We then tested mice on the elevated zero maze and the tail suspension tests, respective tests of anxiety- and depression-like behavior. Contrary to our initial hypothesis, naloxone potentiated the anxiolytic-like, but not the antidepressant-like, effect of oxytocin. Using a selective μ-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, and a selective κ-opioid receptor antagonist, norbinaltorphimine, we demonstrate that μ-opioid receptor blockade potentiated the anxiolytic-like effect of oxytocin, whereas κ-opioid receptor blockade inhibited the oxytocin-induced anxiolytic-like effects. The present results suggest that endogenous opioids can regulate the oxytocin system to modulate anxiety-like behavior. Potential clinical implications of these findings are discussed.
2023
Marchette, Renata C N; Carlson, Erika R; Said, Nadia; Koob, George F; Vendruscolo, Leandro F
In: Addict Neurosci, vol. 5, 2023, ISSN: 2772-3925.
@article{pmid36683829,
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}
}
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.
2022
Farokhnia, Mehdi; Rentsch, Christopher T; Chuong, Vicky; McGinn, M Adrienne; Elvig, Sophie K; Douglass, Eliza A; Gonzalez, Luis A; Sanfilippo, Jenna E; Marchette, Renata C N; Tunstall, Brendan J; Fiellin, David A; Koob, George F; Justice, Amy C; Leggio, Lorenzo; Vendruscolo, Leandro F
Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies Journal Article
In: Mol Psychiatry, vol. 27, no. 11, pp. 4642–4652, 2022, ISSN: 1476-5578.
@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}
}
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.
Alvarez-Bagnarol, Yocasta; Marchette, Renata C N; Francis, Chase; Morales, Marisela M; Vendruscolo, Leandro F
Neuronal Correlates of Hyperalgesia and Somatic Signs of Heroin Withdrawal in Male and Female Mice Journal Article
In: eNeuro, vol. 9, no. 4, 2022, ISSN: 2373-2822.
@article{pmid35728954,
title = {Neuronal Correlates of Hyperalgesia and Somatic Signs of Heroin Withdrawal in Male and Female Mice},
author = {Yocasta Alvarez-Bagnarol and Renata C N Marchette and Chase Francis and Marisela M Morales and Leandro F Vendruscolo},
url = {https://pubmed.ncbi.nlm.nih.gov/35728954/},
doi = {10.1523/ENEURO.0106-22.2022},
issn = {2373-2822},
year = {2022},
date = {2022-06-01},
urldate = {2022-06-01},
journal = {eNeuro},
volume = {9},
number = {4},
abstract = {Opioid withdrawal involves the manifestation of motivational and somatic symptoms. However, the brain structures that are involved in the expression of different opioid withdrawal signs remain unclear. We induced opioid dependence by repeatedly injecting escalating heroin doses in male and female C57BL/6J mice. We assessed hyperalgesia during spontaneous heroin withdrawal and somatic signs of withdrawal that was precipitated by the preferential µ-opioid receptor antagonist naloxone. Heroin-treated mice exhibited significantly higher hyperalgesia and somatic signs than saline-treated mice. Following behavioral assessment, we measured regional changes in brain activity by automated the counting of c-Fos expression (a marker of cellular activity). Using Principal Component Analysis, we determined the association between behavior (hyperalgesia and somatic signs of withdrawal) and c-Fos expression in different brain regions. Hyperalgesia was associated with c-Fos expression in the lateral hypothalamus, central nucleus of the amygdala, ventral tegmental area, parabrachial nucleus, dorsal raphe, and locus coeruleus. Somatic withdrawal was associated with c-Fos expression in the paraventricular nucleus of the thalamus, lateral habenula, dorsal raphe, and locus coeruleus. Thus, hyperalgesia and somatic withdrawal signs were each associated with c-Fos expression in unique sets of brain areas. The expression of c-Fos in the dorsal raphe and locus coeruleus was associated with both hyperalgesia and somatic withdrawal. Understanding common neurobiological mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of opioid use disorder.The public impact of the opioid crisis has prompted an effort to understand the neurobiological mechanisms of opioid use disorder (OUD). The need to avoid withdrawal symptoms is hypothesized to drive compulsive drug-taking and -seeking in OUD. Thus, understanding the mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of OUD. We reported brain structures that are associated with the expression of hyperalgesia and somatic signs of opioid withdrawal in male and female heroin-dependent mice. Hyperalgesia during spontaneous opioid withdrawal and somatic withdrawal resulted in c-Fos expression in autonomic and limbic brain regions. The expression of c-Fos in the dorsal raphe and locus coeruleus were associated with both hyperalgesia and somatic withdrawal.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Opioid withdrawal involves the manifestation of motivational and somatic symptoms. However, the brain structures that are involved in the expression of different opioid withdrawal signs remain unclear. We induced opioid dependence by repeatedly injecting escalating heroin doses in male and female C57BL/6J mice. We assessed hyperalgesia during spontaneous heroin withdrawal and somatic signs of withdrawal that was precipitated by the preferential µ-opioid receptor antagonist naloxone. Heroin-treated mice exhibited significantly higher hyperalgesia and somatic signs than saline-treated mice. Following behavioral assessment, we measured regional changes in brain activity by automated the counting of c-Fos expression (a marker of cellular activity). Using Principal Component Analysis, we determined the association between behavior (hyperalgesia and somatic signs of withdrawal) and c-Fos expression in different brain regions. Hyperalgesia was associated with c-Fos expression in the lateral hypothalamus, central nucleus of the amygdala, ventral tegmental area, parabrachial nucleus, dorsal raphe, and locus coeruleus. Somatic withdrawal was associated with c-Fos expression in the paraventricular nucleus of the thalamus, lateral habenula, dorsal raphe, and locus coeruleus. Thus, hyperalgesia and somatic withdrawal signs were each associated with c-Fos expression in unique sets of brain areas. The expression of c-Fos in the dorsal raphe and locus coeruleus was associated with both hyperalgesia and somatic withdrawal. Understanding common neurobiological mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of opioid use disorder.The public impact of the opioid crisis has prompted an effort to understand the neurobiological mechanisms of opioid use disorder (OUD). The need to avoid withdrawal symptoms is hypothesized to drive compulsive drug-taking and -seeking in OUD. Thus, understanding the mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of OUD. We reported brain structures that are associated with the expression of hyperalgesia and somatic signs of opioid withdrawal in male and female heroin-dependent mice. Hyperalgesia during spontaneous opioid withdrawal and somatic withdrawal resulted in c-Fos expression in autonomic and limbic brain regions. The expression of c-Fos in the dorsal raphe and locus coeruleus were associated with both hyperalgesia and somatic withdrawal.
Carmack, Stephanie A; Vendruscolo, Janaina C M; McGinn, M Adrienne; Miranda-Barrientos, Jorge; Repunte-Canonigo, Vez; Bosse, Gabriel D; Mercatelli, Daniele; Giorgi, Federico M; Fu, Yu; Hinrich, Anthony J; Jodelka, Francine M; Ling, Karen; Messing, Robert O; Peterson, Randall T; Rigo, Frank; Edwards, Scott; Sanna, Pietro P; Morales, Marisela; Hastings, Michelle L; Koob, George F; Vendruscolo, Leandro F
Corticosteroid sensitization drives opioid addiction Journal Article
In: Mol Psychiatry, 2022, ISSN: 1476-5578.
@article{pmid35296810,
title = {Corticosteroid sensitization drives opioid addiction},
author = {Stephanie A Carmack and Janaina C M Vendruscolo and M Adrienne McGinn and Jorge Miranda-Barrientos and Vez Repunte-Canonigo and Gabriel D Bosse and Daniele Mercatelli and Federico M Giorgi and Yu Fu and Anthony J Hinrich and Francine M Jodelka and Karen Ling and Robert O Messing and Randall T Peterson and Frank Rigo and Scott Edwards and Pietro P Sanna and Marisela Morales and Michelle L Hastings and George F Koob and Leandro F Vendruscolo},
url = {https://pubmed.ncbi.nlm.nih.gov/35296810/},
doi = {10.1038/s41380-022-01501-1},
issn = {1476-5578},
year = {2022},
date = {2022-03-01},
urldate = {2022-03-01},
journal = {Mol Psychiatry},
abstract = {The global crisis of opioid overdose fatalities has led to an urgent search to discover the neurobiological mechanisms of opioid use disorder (OUD). A driving force for OUD is the dysphoric and emotionally painful state (hyperkatifeia) that is produced during acute and protracted opioid withdrawal. Here, we explored a mechanistic role for extrahypothalamic stress systems in driving opioid addiction. We found that glucocorticoid receptor (GR) antagonism with mifepristone reduced opioid addiction-like behaviors in rats and zebrafish of both sexes and decreased the firing of corticotropin-releasing factor neurons in the rat amygdala (i.e., a marker of brain stress system activation). In support of the hypothesized role of glucocorticoid transcriptional regulation of extrahypothalamic GRs in addiction-like behavior, an intra-amygdala infusion of an antisense oligonucleotide that blocked GR transcriptional activity reduced addiction-like behaviors. Finally, we identified transcriptional adaptations of GR signaling in the amygdala of humans with OUD. Thus, GRs, their coregulators, and downstream systems may represent viable therapeutic targets to treat the "stress side" of OUD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The global crisis of opioid overdose fatalities has led to an urgent search to discover the neurobiological mechanisms of opioid use disorder (OUD). A driving force for OUD is the dysphoric and emotionally painful state (hyperkatifeia) that is produced during acute and protracted opioid withdrawal. Here, we explored a mechanistic role for extrahypothalamic stress systems in driving opioid addiction. We found that glucocorticoid receptor (GR) antagonism with mifepristone reduced opioid addiction-like behaviors in rats and zebrafish of both sexes and decreased the firing of corticotropin-releasing factor neurons in the rat amygdala (i.e., a marker of brain stress system activation). In support of the hypothesized role of glucocorticoid transcriptional regulation of extrahypothalamic GRs in addiction-like behavior, an intra-amygdala infusion of an antisense oligonucleotide that blocked GR transcriptional activity reduced addiction-like behaviors. Finally, we identified transcriptional adaptations of GR signaling in the amygdala of humans with OUD. Thus, GRs, their coregulators, and downstream systems may represent viable therapeutic targets to treat the "stress side" of OUD.
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,
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}
}
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.
Wiers, Corinde E; Vendruscolo, Leandro F; van der Veen, Jan-Willem; Manza, Peter; Shokri-Kojori, Ehsan; Kroll, Danielle S; Feldman, Dana E; McPherson, Katherine L; Biesecker, Catherine L; Zhang, Rui; Herman, Kimberly; Elvig, Sophie K; Vendruscolo, Janaina C M; Turner, Sara A; Yang, Shanna; Schwandt, Melanie; Tomasi, Dardo; Cervenka, Mackenzie C; Fink-Jensen, Anders; Benveniste, Helene; Diazgranados, Nancy; Wang, Gene-Jack; Koob, George F; Volkow, Nora D
Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents Journal Article
In: Sci Adv, vol. 7, no. 15, 2021, ISSN: 2375-2548.
@article{pmid33837086,
title = {Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents},
author = {Corinde E Wiers and Leandro F Vendruscolo and Jan-Willem van der Veen and Peter Manza and Ehsan Shokri-Kojori and Danielle S Kroll and Dana E Feldman and Katherine L McPherson and Catherine L Biesecker and Rui Zhang and Kimberly Herman and Sophie K Elvig and Janaina C M Vendruscolo and Sara A Turner and Shanna Yang and Melanie Schwandt and Dardo Tomasi and Mackenzie C Cervenka and Anders Fink-Jensen and Helene Benveniste and Nancy Diazgranados and Gene-Jack Wang and George F Koob and Nora D Volkow},
url = {https://pubmed.ncbi.nlm.nih.gov/33837086/},
doi = {10.1126/sciadv.abf6780},
issn = {2375-2548},
year = {2021},
date = {2021-04-01},
urldate = {2021-04-01},
journal = {Sci Adv},
volume = {7},
number = {15},
abstract = {Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD ( = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet ( = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD ( = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet ( = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.
2020
Moussawi, K; Ortiz, M M; Gantz, S C; Tunstall, B J; Marchette, R C N; Bonci, A; Koob, G F; Vendruscolo, L F
Fentanyl vapor self-administration model in mice to study opioid addiction. Journal Article
In: Sci Adv, vol. 6, no. 32, pp. eabc0413, 2020.
@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}
}
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.
2019
Tunstall, Brendan J; Kirson, Dean; Zallar, Lia J; McConnell, Sam A; Vendruscolo, Janaina C M; Ho, Chelsea P; Oleata, Christopher S; Khom, Sophia; Manning, Maurice; Lee, Mary R; Leggio, Lorenzo; Koob, George F; Roberto, Marisa; Vendruscolo, Leandro F
In: PLoS Biol, vol. 17, no. 4, pp. e2006421, 2019, ISSN: 1545-7885 (Electronic); 1544-9173 (Linking).
@article{Tunstall:2019aa,
title = {Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala.},
author = {Brendan J Tunstall and Dean Kirson and Lia J Zallar and Sam A McConnell and Janaina C M Vendruscolo and Chelsea P Ho and Christopher S Oleata and Sophia Khom and Maurice Manning and Mary R Lee and Lorenzo Leggio and George F Koob and Marisa Roberto and Leandro F Vendruscolo},
url = {https://www.ncbi.nlm.nih.gov/pubmed/30990816},
doi = {10.1371/journal.pbio.2006421},
issn = {1545-7885 (Electronic); 1544-9173 (Linking)},
year = {2019},
date = {2019-04-16},
urldate = {2019-04-16},
journal = {PLoS Biol},
volume = {17},
number = {4},
pages = {e2006421},
address = {Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America.},
abstract = {Oxytocin administration has been reported to decrease consumption, withdrawal, and drug-seeking associated with several drugs of abuse and thus represents a promising pharmacological approach to treat drug addiction. We used an established rat model of alcohol dependence to investigate oxytocin's effects on dependence-induced alcohol drinking, enhanced motivation for alcohol, and altered GABAergic transmission in the central nucleus of the amygdala (CeA). Intraperitoneal oxytocin administration blocked escalated alcohol drinking and the enhanced motivation for alcohol in alcohol-dependent but not nondependent rats. Intranasal oxytocin delivery fully replicated these effects. Intraperitoneal administration had minor but significant effects of reducing locomotion and intake of non-alcoholic palatable solutions, whereas intranasal oxytocin administration did not. In dependent rats, intracerebroventricular administration of oxytocin or the oxytocin receptor agonist PF-06655075, which does not cross the blood-brain barrier (i.e., it would not diffuse to the periphery), but not systemic administration of PF-06655075 (i.e., it would not reach the brain), decreased alcohol drinking. Administration of a peripherally restricted oxytocin receptor antagonist did not reverse the effect of intranasal oxytocin on alcohol drinking. Ex vivo electrophysiological recordings from CeA neurons indicated that oxytocin decreases evoked GABA transmission in nondependent but not in dependent rats, whereas oxytocin decreased the amplitude of spontaneous GABAergic responses in both groups. Oxytocin blocked the facilitatory effects of acute alcohol on GABA release in the CeA of dependent but not nondependent rats. Together, these results provide converging evidence that oxytocin specifically and selectively blocks the enhanced motivation for alcohol drinking that develops in alcohol dependence likely via a central mechanism that may result from altered oxytocin effects on CeA GABA transmission in alcohol dependence. Neuroadaptations in endogenous oxytocin signaling may provide a mechanism to further our understanding of alcohol use disorder.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Oxytocin administration has been reported to decrease consumption, withdrawal, and drug-seeking associated with several drugs of abuse and thus represents a promising pharmacological approach to treat drug addiction. We used an established rat model of alcohol dependence to investigate oxytocin's effects on dependence-induced alcohol drinking, enhanced motivation for alcohol, and altered GABAergic transmission in the central nucleus of the amygdala (CeA). Intraperitoneal oxytocin administration blocked escalated alcohol drinking and the enhanced motivation for alcohol in alcohol-dependent but not nondependent rats. Intranasal oxytocin delivery fully replicated these effects. Intraperitoneal administration had minor but significant effects of reducing locomotion and intake of non-alcoholic palatable solutions, whereas intranasal oxytocin administration did not. In dependent rats, intracerebroventricular administration of oxytocin or the oxytocin receptor agonist PF-06655075, which does not cross the blood-brain barrier (i.e., it would not diffuse to the periphery), but not systemic administration of PF-06655075 (i.e., it would not reach the brain), decreased alcohol drinking. Administration of a peripherally restricted oxytocin receptor antagonist did not reverse the effect of intranasal oxytocin on alcohol drinking. Ex vivo electrophysiological recordings from CeA neurons indicated that oxytocin decreases evoked GABA transmission in nondependent but not in dependent rats, whereas oxytocin decreased the amplitude of spontaneous GABAergic responses in both groups. Oxytocin blocked the facilitatory effects of acute alcohol on GABA release in the CeA of dependent but not nondependent rats. Together, these results provide converging evidence that oxytocin specifically and selectively blocks the enhanced motivation for alcohol drinking that develops in alcohol dependence likely via a central mechanism that may result from altered oxytocin effects on CeA GABA transmission in alcohol dependence. Neuroadaptations in endogenous oxytocin signaling may provide a mechanism to further our understanding of alcohol use disorder.
Carmack, Stephanie A; Keeley, Robin J; Vendruscolo, Janaina Cm; Lowery-Gionta, Emily G; Lu, Hanbing; Koob, George F; Stein, Elliot A; Vendruscolo, Leandro F
Heroin addiction engages negative emotional learning brain circuits in rats. Journal Article
In: J Clin Invest, vol. 130, 2019, ISSN: 1558-8238 (Electronic); 0021-9738 (Linking).
@article{Carmack:2019aa,
title = {Heroin addiction engages negative emotional learning brain circuits in rats.},
author = {Stephanie A Carmack and Robin J Keeley and Janaina Cm Vendruscolo and Emily G Lowery-Gionta and Hanbing Lu and George F Koob and Elliot A Stein and Leandro F Vendruscolo},
url = {https://www.ncbi.nlm.nih.gov/pubmed/30913040},
doi = {10.1172/JCI125534},
issn = {1558-8238 (Electronic); 0021-9738 (Linking)},
year = {2019},
date = {2019-03-26},
journal = {J Clin Invest},
volume = {130},
abstract = {Opioid use disorder (OUD) is associated with the emergence of persistent negative emotional states during drug abstinence that drive compulsive drug taking and seeking. Functional magnetic resonance imaging (fMRI) in rats identified neurocircuits that were activated by stimuli that were previously paired with heroin withdrawal. The activation of amygdala and hypothalamic circuits was related to the degree of heroin dependence, supporting the significance of conditioned negative affect in sustaining compulsive-like heroin seeking and taking and providing neurobiological insights into the drivers of the current opioid crisis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Opioid use disorder (OUD) is associated with the emergence of persistent negative emotional states during drug abstinence that drive compulsive drug taking and seeking. Functional magnetic resonance imaging (fMRI) in rats identified neurocircuits that were activated by stimuli that were previously paired with heroin withdrawal. The activation of amygdala and hypothalamic circuits was related to the degree of heroin dependence, supporting the significance of conditioned negative affect in sustaining compulsive-like heroin seeking and taking and providing neurobiological insights into the drivers of the current opioid crisis.
2015
Vendruscolo, Leandro F; Estey, David; Goodell, Vivian; Macshane, Lauren G; Logrip, Marian L; Schlosburg, Joel E; McGinn, Adrienne M; Zamora-Martinez, Eva R; Belanoff, Joseph K; Hunt, Hazel J; Sanna, Pietro P; George, Olivier; Koob, George F; Edwards, Scott; Mason, Barbara J
Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. Journal Article
In: J Clin Invest, vol. 125, no. 8, pp. 3193-3197, 2015.
@article{Vendruscolo:2015kt,
title = {Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals.},
author = {Leandro F Vendruscolo and David Estey and Vivian Goodell and Lauren G Macshane and Marian L Logrip and Joel E Schlosburg and Adrienne M McGinn and Eva R Zamora-Martinez and Joseph K Belanoff and Hazel J Hunt and Pietro P Sanna and Olivier George and George F Koob and Scott Edwards and Barbara J Mason},
url = {https://pubmed.ncbi.nlm.nih.gov/26121746/},
doi = {10.1172/JCI79828},
year = {2015},
date = {2015-08-03},
urldate = {2015-08-03},
journal = {J Clin Invest},
volume = {125},
number = {8},
pages = {3193-3197},
abstract = {Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone-treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone-treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism.
2014
Koob, George F; Buck, Cara L; Cohen, Ami; Edwards, Scott; Park, Paula E; Schlosburg, Joel E; Schmeichel, Brooke; Vendruscolo, Leandro F; Wade, Carrie L; Whitfield, Timothy W; George, Olivier
Addiction as a stress surfeit disorder Journal Article
In: Neuropharmacology, vol. 76 Pt B, no. 0 0, pp. 370–382, 2014, ISSN: 1873-7064.
@article{pmid23747571,
title = {Addiction as a stress surfeit disorder},
author = {George F Koob and Cara L Buck and Ami Cohen and Scott Edwards and Paula E Park and Joel E Schlosburg and Brooke Schmeichel and Leandro F Vendruscolo and Carrie L Wade and Timothy W Whitfield and Olivier George},
url = {https://pubmed.ncbi.nlm.nih.gov/23747571/},
doi = {10.1016/j.neuropharm.2013.05.024},
issn = {1873-7064},
year = {2014},
date = {2014-01-01},
urldate = {2014-01-01},
journal = {Neuropharmacology},
volume = {76 Pt B},
number = {0 0},
pages = {370--382},
abstract = {Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-κ opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-κ opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
2012
Vendruscolo, Leandro F; Barbier, Estelle; Schlosburg, Joel E; Misra, Kaushik K; Whitfield, Timothy W; Logrip, Marian L; Rivier, Catherine; Repunte-Canonigo, Vez; Zorrilla, Eric P; Sanna, Pietro P; Heilig, Markus; Koob, George F
Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats Journal Article
In: J Neurosci, vol. 32, no. 22, pp. 7563–7571, 2012, ISSN: 1529-2401.
@article{pmid22649234,
title = {Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats},
author = {Leandro F Vendruscolo and Estelle Barbier and Joel E Schlosburg and Kaushik K Misra and Timothy W Whitfield and Marian L Logrip and Catherine Rivier and Vez Repunte-Canonigo and Eric P Zorrilla and Pietro P Sanna and Markus Heilig and George F Koob},
url = {https://pubmed.ncbi.nlm.nih.gov/22649234/},
doi = {10.1523/JNEUROSCI.0069-12.2012},
issn = {1529-2401},
year = {2012},
date = {2012-05-01},
urldate = {2012-05-01},
journal = {J Neurosci},
volume = {32},
number = {22},
pages = {7563--7571},
abstract = {Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.
