CPN (Section Chief: Lorenzo Leggio, M.D., Ph.D., M.Sc.) Joint NIAAA-NIDA Annual Report 2018 The joint NIAAA-NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN) conducts translational and clinical inpatient and outpatient studies to identify possible novel medications for addiction. Under the leadership of Lorenzo Leggio, M.D., Ph.D., M.Sc., 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 to shed light on the possible role of the gut-liver-brain axis in alcohol use disorder (AUD). 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 concentrations 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: Zallar et al. 2017). 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. Main results indicate that IV ghrelin increases number of infusions during the IV alcohol self-administration and modulates brain activity during a fMRI session (Farokhnia et al., Molecular Psychiatry in press). Furthermore, a secondary analysis indicates that IV ghrelin reduces hangover the day after (Farokhnia et al., Pharmacology, Biochemistry and Behavior in press). Contrary to animal studies, the hypothesis that GHS-R1a antagonism results in reduced alcohol use has never been tested in humans. 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 AUD. 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 study 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 recently published. The main results indicate that this GHS-R1a inverse agonist is safe and tolerable, when co-administered with alcohol and does not affect alcohol PK (Lee et al., Molecular Psychiatry in press). Very preliminary results also suggest that this compound reduces alcohol- and food-cue induced cravings in our bar-lab (Lee et al., Molecular Psychiatry in press). A Phase 2a clinical study (protocol 16-AA-0080) is currently ongoing. Furthermore, we have recently developed a novel GHS-R global knock-out rat model, in collaboration with PIs of the NIDA IRP (Drs. Brandon Harvey, Leandro Vendruscolo and George Koob). This model has been characterized from a histology, neuroendocrine and behavioral standpoint (Zallar et al., International Journal of Obesity 2018). Additional work using this KO rat model is ongoing. 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). We have recently conducted two human post-mortem brain studies where we have described oxytocin and oxytocin receptor expression in individuals with alcohol dependence using the Australian brain bank (Lee et al., Psychoneuroendocrinology 2017) and in individuals with mental disorders in collaboration with Dr. Barbara Lipskas NIHM Core (Lee et al., Psychoneuroendocrinology 2018). Increasing evidence suggests a role of the gut microbiota in neuropsychiatric disorders. Clinical and translational research has suggested a causality link between the gut microbiota and symptoms of anxiety, depression and autism (reviewed in: Dinan and Cryan, 2016). A recent study suggests that changes in the gut microbiota 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 et al., Alcohol and Alcoholism 2017) indicates that the understanding of the role of the gut microbiota 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 microbiota in AUD. Dr. Leggio received a grant award from the Peter G. Dodge Foundation to partially support this study. This clinical study (17-AA-0093) and preclinical experiments are currently ongoing. Finally, additional smaller projects have been completed: 1) we have conducted a sweet preference test in individuals with alcohol dependence and provided further support for the role of sweet liking phenotype in identifying subpopulations. These findings also point to the importance of how sweet likers are defined, therefore highlighting the need for further research (Bouhlal et al., Alcohol and Alcoholism 2018); 2) we have shown that pharmacological manipulation of the GABA system via GABA-B receptor agonism (baclofen) leads to change in feeding- and stress-related neuroendocrine pathways (Farokhnia et al., Neuropharmacology 2018); 3) we have also described that, overall adult ADHD symptoms, and more specifically, symptoms of hyperactivity/restlessness and problems with self-concept, increased the odds of receiving a diagnosis of alcohol dependence (AD). Within the AD sample, we found that impulsivity mediated the relationship between adult ADHD symptoms and AD severity. In particular, negative and positive urgency meditated the relationship of overall adult ADHD symptoms, and symptoms of hyperactivity/restlessness and problems with self-concept with AD severity (Daurio et al., Alcoholism: Clinical and Experimental Research 2018); and 4) in collaboration with Marilyn Huestis (NIDA IRP), we have also reported a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses (Bouhlal et al., Drug and Alcohol Dependence 2018).
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