GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence

REVIEW ARTICLE published: 06 June 2014 doi: 10.3389/fnins.2014.00140 GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence Roberta Agabio 1 and Giancarlo Colombo 2* 1 2 Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy Section of Cagliari, Neuroscience Institute, National Research Council of Italy, Monserrato, Italy Edited by: Richard Lowell Bell, Indiana University School of Medicine, USA Reviewed by: David A. Slattery, University of Regensburg, Germany Gopalkumar Rakesh, State University of New York System, USA *Correspondence: Giancarlo Colombo, Neuroscience Institute, Section of Cagliari, National Research Council of Italy, S.S. 554, km. 4,500, Monserrato, Italy e-mail: The present paper summarizes the preclinical and clinical studies conducted to define the “anti-alcohol” pharmacological profile of the prototypic GABAB receptor agonist, baclofen, and its therapeutic potential for treatment of alcohol use disorder (AUD). Numerous studies have reported baclofen-induced suppression of alcohol drinking (including relapse- and binge-like drinking) and alcohol reinforcing, motivational, stimulating, and rewarding properties in rodents and monkeys. The majority of clinical surveys conducted to date—including case reports, retrospective chart reviews, and randomized placebo-controlled studies—suggest the ability of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. The recent identification of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, represents a novel, and likely more favorable, option for pharmacological manipulations of the GABAB receptor. Accordingly, data collected to date suggest that positive allosteric modulators of the GABAB receptor reproduce several “anti-alcohol” effects of baclofen and display a higher therapeutic index (with larger separation—in terms of doses—between “anti-alcohol” effects and sedation). Keywords: GABAB receptor, baclofen, positive allosteric modulators, alcohol use disorder, animal models of alcohol use disorder INTRODUCTION Alcohol abuse and dependence are severe mental disorders characterized by bouts of compulsive and uncontrolled alcohol consumption, and an inability to cut down drinking despite the knowledge of its negative consequences (American Psychiatric Association, 2000). These frequent disorders are related to chronic medical conditions, car crashes, domestic violence, fetal alcohol syndrome, neuropsychological impairment, economic costs, loss of productivity, and psychiatric comorbidity (see Rehm et al., 2009; Nutt et al., 2010). Up to the penultimate edition of the Diagnostic and Statistical Manual of Mental Disorders (DSMIV-TR) (American Psychiatric Association, 2000), alcohol abuse and dependence were classified as independent alcohol use disorders (AUDs); in the last DSM edition (DSM-5), they have been joined into a single mental disorder, alcohol use disorder, or AUD (American Psychiatric Association, 2013). Diagnostic criteria for AUD include those listed for the diagnosis of dependence and abuse, together with a new criterion, a subjective experience of wanting to consume alcohol, also defined “craving” (Tiffany and Wray, 2012). The aims of AUD treatment consist in achieving abstinence, or reducing alcohol consumption, reducing the frequency and severity of relapses, and improving psychological and social functioning. The process involved in acquiring and maintaining abstinence from alcohol may require a first phase known as “detoxification” aimed at decreasing withdrawal symptoms (when present), and a second “rehabilitation” phase, aimed at www.frontiersin.org maintaining the motivation to abstain, developing an alcohol-free lifestyle, and reducing the risk of relapse. Treatment to achieve these aims includes psychological and pharmacological therapies. Psychological and social interventions (including Alcoholics Anonymous and various counseling approaches) are usually considered core treatment options (see Schuckit, 2009). However, these approaches have demonstrated only a moderate success rate. Pharmacotherapy should be used to increase the efficacy of nonpharmacological approaches. Unfortunately, the few available AUD medications display only moderate efficacy, with several limitations to their clinical use, including poor compliance and even abuse liability (see Chick and Nutt, 2012; see Franck and Jayaram-Lindström, 2013). Over the last 15 years, multiple lines of experimental and clinical evidence have suggested a role for the GABAB receptor in the control of several alcohol-related behaviors (for reviews on the GABAB receptor, see Bettler et al., 2004; Couve et al., 2004; Emson, 2007). Pharmacological activation of the orthosteric binding site of the GABAB receptor has repeatedly been reported to suppress alcohol drinking and alcohol withdrawal syndrome (AWS) in rodents and human alcoholics, as well as alcohol reinforcing and motivational properties in rodents and non-human primates and craving for alcohol in human alcoholics. These data have led to the development of the prototypic GABAB receptor agonist, baclofen (used for more than 50 years in the treatment of spasticity), as a promising, novel pharmacotherapy for AUD. June 2014 | Volume 8 | Article 140 | 1 Agabio and Colombo More recently, identification of a binding site of positive allosteric modulation (topographically distinct from the orthosteric binding site) has provided a new strategy for pharmacological manipulation of the GABAB neurotransmission. Activation of this binding site—by a class of agents known as positive allosteric modulators of the GABAB receptor (GABAB PAMs)— augments the affinity of the GABAB receptor for GABA and agonists and synergistically potentiates their effects (see Froestl, 2010). GABAB PAMs are devoid of substantial intrinsic agonistic activity in the absence of GABA; they do not perturb receptor signaling on their own, but potentiate the effect of GABA only in those synapses where and when endogenous GABA has been released (see Froestl, 2010). Accordingly, GABAB PAMs are expected to produce fewer side effects and lower tolerance. Rodent data confirm that GABAB PAMs reproduced several in vivo effects of baclofen, displaying a notably larger separation between the “desired” pharmacological effects (e.g.: anxiolysis, “anti-addictive” effects) and “unwanted,” or adverse, effects (e.g., sedation, motor-incoordination). For these reasons, GABAB PAMs currently represent a major step forward in the pharmacology of the GABAB receptor. The present paper is aimed at reviewing the lines of preclinical and clinical evidence featuring baclofen and GABAB PAMs as potentially effective pharmacotherapies for AUD. PRECLINICAL DATA BACLOFEN The vast majority of data presently available have been collected with bacl (...truncated)