Our joint NIAAA-NIDA joint lab is currently conducting four main projects, as detailed next. Baclofen Project The GABA-B receptor agonist baclofen has been identified as a medication able to reduce alcohol craving and intake in alcoholic individuals. Consistent with preclinical studies, clinical studies have demonstrated baclofen's effects in reducing alcohol craving and intake (Addolorato et al, Lancet 2007, Leggio et al, Addict Behav 2012, Pharmacol Biochem Behav 2013), especially in alcoholic patients with liver disease, as we recently reviewed (Lee and Leggio, Am J Psychiatry in press). However, one trial found a robust treatment effect, but no differences between baclofen and placebo (Garbutt et al, ACER 2010). This suggests that different alcoholic individuals may respond differently to baclofen. For example, we recentyl reported baclofen effect in increasing alcohol-tobacco co-abstinence in alcoholic smokers (Leggio et al, Psychopharmacol 2015). Baclofen has also been demonstrated to reduce anxiety in alcoholic patients, and alcoholic patients with higher levels of anxiety may represent a sub-population responsive to baclofen treatment (Leggio et al, CNS Neurol Disord Drug Targets 2010). We also conducted an analysis in collaboration with Haber lab in Sydney that further support the role of anxiety on baclofen effects on drinking (Morley et,Alcohol and Alcohol 2014) Thus, we developed a clinical protocol (AA-13-0040) that is testing the role of baclofen on alcohol-related outcomes in anxious alcoholic individuals. Dr. Leggio received a NARSAD Award for this study. Ghrelin Project Ghrelin is a 28-amino acid peptide acting as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Animal experiments demonstrate that the central ghrelin action not only stimulates the reward processing but is also required for stimulation of that system by alcohol (Jerlhag et al., PNAS 2009; Suchankova et al., PLoS One 2013). Human studies show a positive correlation between ghrelin level and alcohol craving scores. Recently, we reported that intravenous ghrelin acutely increases alcohol craving in alcoholic individuals (Leggio et al, Biol Psychiatry 2014). There are three studies conducted or under way within this theme of the CPN Section research agenda. a. We recently reported that IV ghrelin acutely reduces blood leptin levels and changes in leptin levels correlate with urge to drink alcohol (Haass-Koffler et al. Transl Psychiatry in press) b. We are currently conducting a within-subject, double-blind, placebo-controlled human laboratory study (AA-13-0043) whose primary objectives are 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. c. Unlike in rodents, the hypothesis that GHS-R antagonism results in reduced alcohol use as never been tested in humans. In order to test this hypothesis, we have developed a translational project that will assess the role of a GHS-R antagonist manufactured by Pfizer as a novel medication for alcoholism. This project was developed by Dr. Leggio in collaboration with Fatemeh Akhlaghi, Pharm.D., Ph.D., from URI and was awarded with a NCATS grant award. This project will allow us to generate preliminary evidence on the safety and efficacy of such pharmacological agent via three projects, i.e.: (P1) a set of experiments testing the safety of the drug/alcohol interactions; (P2) a drug/alcohol interaction study to establish safety in humans (Phase 1b); and (P3) a human laboratory proof-of-concept study to assess the efficacy of this drug on alcohol-seeking behaviors (Phase 2a). These are conducted at the NIH Intramural Program under the leadership of Dr. Lorenzo Leggio. Assays to measure the study drug were developed and validated in Akhlaghi's lab and we recently published the methodology (Ghareeb et al, Anal Bioanal Chem. 2015) c. We are collaborating with the NIDA Optogenetics and Transgenic Technology Core (Dr. Brandon Harvey) in order to develop conditioning knock-in and know-out rat models for the ghrelin receptor. Oxytocin Project Recent research suggests that oxytocin (OT) may play a role in the neurobiology of AUD. Ethanol is a potent inhibitor of OT release and is neurotoxic to OT neurons. The behavioral deficits seen in chronic alcoholics suggest a central deficiency of OT. OT has low abuse liability and modulates a number of key systems involved in addiction processes, including dopamine (DA) mesolimbic reward circuitry. In animals, OT administration produced long-term decreases in alcohol reinforcement, decreased alcohol seeking during abstinence, attenuated drug tolerance, and decreased withdrawal symptoms. Furthermore, a pilot clinical study suggests a role of OT in reducing alcohol withdrawal symptoms and craving in alcoholic patients undergoing a detox. Dr. Mary Lee, MD, Staff Clinician in Dr. Leggios CPN Section was recently awarded with one of the NIH B2B Award to conduct translational studies on the role of OT in alcohol and drug addiction. The overall goal of this translational project is threefold: to demonstrate the effect, in subjects with AUD of intranasal OT on 1) alcohol cue-induced craving and self-administration, 2) alcohol induced striatal DA release and, 3) in a parallel preclinical study, to investigate the brain penetrance of intranasally-administered OT. The human component (T-AA-0031) will be a within-subject randomized, controlled study. In parallel, we will investigate the penetrance of exogenous intranasal OT into the brain and specific brain regions of binding in monkeys in collaboration with Dr. Bruno Averbeck (NIMH). Additionally, CPN is collaborating with: 1) Drs. Amy Newman and Gigi Tanda (NIDA) to investigate the role of OT in central dopamine release via microdialysis experiments; and 2) Dr. Marilyn Huestis to develop a very sensitive MS assay for OT. GLP-1 Project The glucagon-like peptide-1 (GLP-1) is an incretin involved in the regulation of food intake. Recent preclinical studies have shown that a GLP-1 receptor (GLP1R) agonist, attenuates the reinforcing properties of alcohol in rodents (Egecioglu et al, Psychoneuroendocrinology 2013; Shirazi et al., PLoS One 2013). Given that AUD is a partly heritable, complex, psychiatric disorder, the Section designed a study aimed to investigate whether single nucleotide polymorphisms (SNPs) in GLP1R are associated with AUD. This study included (4) genetic association components and a reverse translational pharmacological experiment used to probe that GLP1R agonism is associated with reduced alcohol use (this last experiment conducted in collaboration with the NIAAA Extramural Division, Dr. Mark Egli). The main results of this study (Suchankova et al. Transl Psychiatry 2015) indicated that genetic variation in the GLP1R were significantly associated with AUD. Additionally, the preclinical study indicated that GLP1R agonism results in significantly and dose-dependent reduction in alcohol consumption and that this is limited to ethanol-dependent mice. Overall conclusions on the impact of our research: Our approach permits complex, multimodal investigations of the potential efficacy and mechanisms of these therapeutic targets in humans, and allows us to develop candidate drugs that hold promise for successful medications development.