The joint NIAAA-NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN) conducts translational and clinical outpatient and inpatient studies in order to identify possible novel medications for addiction. Under Dr. Lorenzo Leggios leadership, the CPN team is particularly interested in the role of the gut-liver-brain axis in alcohol-seeking behaviors. Both preclinical and human approaches are in progress or under development in order to shed light on the possible role of the gut-liver-brain axis in alcohol use disorder (AUD). Baclofen has been identified as a possible medication able to reduce alcohol craving and intake in alcohol dependent individuals. Preclinical and clinical studies indicated that baclofen is effective in reducing alcohol craving and intake (reviewed in: Farokhnia et al. in press). However, one trial found a robust treatment effect, but no differences between baclofen and placebo (Garbutt et al., 2010). This suggests that alcoholic individuals may respond differently to baclofen, e.g. patients with higher levels of anxiety may respond better to baclofen (Leggio et al., 2010). Thus, the CPN Section developed a clinical protocol (13-AA-0040) to test the role of baclofen on alcohol-related outcomes in alcoholic individuals with high anxiety levels. The design is a between-subject randomized double-blind controlled study with the medication conditions as the between subjects factor. Dr. Leggio received a NARSAD Award from the Brain and Behavior Research Foundation to partially support this study. Data analysis and manuscript preparation (Farokhnia et al.) are under way. Animal experiments demonstrate that central ghrelin administration not only stimulates reward processing but is also required for stimulation of that system by alcohol (Jerlhag et al., 2009; Suchankova et al., 2013). Human studies show a positive correlation between ghrelin levels and alcohol craving scores, and intravenous ghrelin acutely increases alcohol craving in individuals suffering with AUD. Together, preclinical and clinical studies suggest that ghrelin might represent a novel pharmacological target for treatment (reviewed in: Leggio, 2010). A within-subject, double-blind, placebo-controlled human laboratory study (protocol 13--AA-0043) was developed by the CPN Section to investigate whether IV ghrelin, as compared to placebo, increases motivation for alcohol reward, as measured by a progressive ratio schedule paradigm with IV alcohol self-infusion; and whether IV ghrelin, as compared to placebo, will increase the BOLD activation in the ventral striatum during an fMRI session. Contrary to animal studies, the hypothesis that GHS-R1a antagonism results in reduced alcohol use as never been tested in humans. In order to test this hypothesis, the CPN Section developed a translational project to assess the role of a GHS-R1a antagonist manufactured by Pfizer as a novel medication for alcoholism. This project was developed in collaboration with Fatemeh Akhlaghi, Pharm.D., Ph.D., from the University of Rhode Island and was recently awarded with a NCATS grant award (UH2/UH3 TR000963) to partially support this project. This project is conducted at the NIH Intramural Research Program under Dr. Leggios leadership; pharmacokinetics (PK)/pharmacodynamic (PD) investigations are conducted in Dr. Akhlaghis lab. A Phase 1b clinical study (protocol 14-AA-0042) was completed and a Phase 2a clinical study (protocol 16-AA-0080) was recently started. Recent research suggests that oxytocin (OT) may play a role in the neurobiology of AUD. In animals, OT administration produces long-term decreases in alcohol reinforcement, decreases alcohol seeking during abstinence, attenuates drug tolerance, and decreases withdrawal symptoms (reviewed in Lee et al. 2016). Dr. Mary Lee, Staff Clinician in Dr. Leggios CPN Section, was awarded an NIH B2B grant award (2014-2015) to partially support this project. Preclinical work in collaboration with NIDA and NIMH basic scientists is close to completion. A clinical study developed by the CPN Section (protocol 16-AA-0082) is planned to start soon. Increasing evidence suggests a role of the gut microbiome in neuropsychiatric disorders. In particular, clinical and translational research has suggested a causality link between the gut microbiome and symptoms of anxiety, depression and autism (reviewed in: Dinan and Cryan, 2016). A recent study suggests that changes in the gut microbiome in patients with AUD and increased gut permeability correlate with alcohol craving. However, the small sample size and the retrospective and self-reported nature of some of the assessments limit the interpretation of these findings. A recent systematic review conducted by our team, (Temko, Bouhlal et al. in preparation) indicates that the understanding of the role of the gut microbiome in AUD is very limited and deserves additional investigation. Therefore, the CPN Section developed a translational and clinical project to investigate the role of the gut microbiome in AUD. Dr. Leggio received a grant award from the Peter G. Dodge Foundation to partially support this study. The clinical study (T-AA-0037) is currently under review.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Alcohol Abuse and Alcoholism
Department
Type
DUNS #
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Haass-Koffler, Carolina L; Goodyear, Kimberly; Zywiak, William H et al. (2018) Corrigendum: Comparing and Combining Topiramate and Aripiprazole on Alcohol-Related Outcomes in a Human Laboratory Study. Alcohol Alcohol 53:500
Zallar, L J; Tunstall, B J; Richie, C T et al. (2018) Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model. Int J Obes (Lond) :
Daurio, Allison M; Aston, Sean A; Schwandt, Melanie L et al. (2018) Impulsive Personality Traits Mediate the Relationship Between Adult Attention-Deficit/Hyperactivity Symptoms and Alcohol Dependence Severity. Alcohol Clin Exp Res 42:173-183
Morris, Laurel S; Voon, Valerie; Leggio, Lorenzo (2018) Stress, Motivation, and the Gut-Brain Axis: A Focus on the Ghrelin System and Alcohol Use Disorder. Alcohol Clin Exp Res :
Bouhlal, Sofia; Farokhnia, Mehdi; Lee, Mary R et al. (2018) Identifying and Characterizing Subpopulations of Heavy Alcohol Drinkers Via a Sucrose Preference Test: A Sweet Road to a Better Phenotypic Characterization? Alcohol Alcohol :
Haass-Koffler, Carolina L; Swift, Robert M; Leggio, Lorenzo (2018) Noradrenergic targets for the treatment of alcohol use disorder. Psychopharmacology (Berl) 235:1625-1634
Lee, M R; Scheidweiler, K B; Diao, X X et al. (2018) Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol Psychiatry 23:115-122
Agabio, Roberta; Sinclair, Julia Ma; Addolorato, Giovanni et al. (2018) Baclofen for the treatment of alcohol use disorder: the Cagliari Statement. Lancet Psychiatry 5:957-960
Farokhnia, Mehdi; Sheskier, Mikela B; Lee, Mary R et al. (2018) Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment. Neuropharmacology 137:230-239
Haass-Koffler, Carolina L; Goodyear, Kimberly; Zywiak, William H et al. (2018) Comparing and Combining Topiramate and Aripiprazole on Alcohol-Related Outcomes in a Human Laboratory Study. Alcohol Alcohol 53:268-276

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