Understanding and Treating Alcohol Craving and Dependence: Recent Pharmacological and Neuroendocrinological Findings

Alcohol & Alcoholism Vol. 44, No. 4, pp. 341–352, 2009 Advance Access publication 18 May 2009 doi: 10.1093/alcalc/agp026 ESBRA-NORDMANN 2008 AWARD LECTURE Understanding and Treating Alcohol Craving and Dependence: Recent Pharmacological and Neuroendocrinological Findings ∗ Lorenzo Leggio1,2, 1 Institute of Internal Medicine, Catholic University of Rome, Rome, Italy and 2 Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA ∗ Corresponding Author: Institute of Internal Medicine, Catholic University of Rome, L.go A. Gemelli 8, I-00168, Rome, Italy. Tel: +39-06-3015-4334; Fax: +39-06-3550-2775; E-mail: (Received 12 February 2009; first review notified 20 February 2009; in revised form 24 March 2009; accepted 20 April 2009; advance access publication 18 May 2009) Abstract — There is a substantial need for discovering innovative ways to provide more information on the neurobiology of alcohol dependence as well as to discover more effective pharmacotherapies for alcohol dependence. Current research includes exploring new pathways able to modulate alcohol craving. In particular, research shows that several neuroendocrinological pathways may be involved in the neurobiology of alcohol craving and dependence. The first part of this review examines recent clinical findings on the role of feeding-related peptides in alcohol craving and dependence. Second, this review focuses on the need to discover new medications that may prove to be safe and effective in the treatment of alcohol dependence. For example, the GABAB receptor has been suggested as a new possible neuropharmacological target in the treatment of alcohol dependence. Accordingly, the second part of this review examines recent clinical findings on the role of the selective GABAB receptor agonist baclofen in the treatment of alcohol-dependent subjects. These two distinct topics will be both analyzed and discussed. The final part of this review discusses possible connections between these two topics, as an example of possible interactions between psychoneuroendocrinology and neuropharmacology. These possible interactions could lead to future intriguing research aimed at understanding and treating alcohol craving and dependence. INTRODUCTION Alcohol craving represents an important theoretical construct in the literature of alcohol dependence. Alcohol craving is generally defined as a strong urge to consume alcohol. It could be thought of as a phenomenon integrating a desire to increase a positive feeling and/or to overcome one that is negative. Craving can occur spontaneously, or it can be elicited by internal or external stimuli known as cues (see Swift, 1999). Internal cues may include emotional states (e.g. anxiety) or symptoms of acute alcohol withdrawal, whereas external cues may include exposure to alcohol-related environments or objects (e.g. bottles of alcoholic beverages or advertisements) (Swift, 1999). The neurobiochemical mechanisms implicated in the etiology of craving involve several neurotransmitters, such as dopamine, gamma-aminobutyric acid (GABA), opioids, glutamate and serotonin (see McBride and Li, 1998; Weiss and Porrino, 2002; Addolorato et al., 2005a; Swift, 2007). The neurobiology of alcohol craving and dependence is extremely complex and not completely understood. Therefore, it is necessary to further elucidate the mechanisms at the basis of alcohol craving as well as the possible presence of factors able to modulate craving itself. It would be beneficial to better understand the mechanisms able to modulate alcohol craving in order to identify new neuropharmacological targets to treat alcohol dependence. Some of the clinical research focused on understanding and treating alcohol craving and dependence may be categorized in two lines of research. (1) Studies focused on the neurobiological mechanisms of alcohol craving: these include studies developing new laboratory paradigms to assess craving; validation of assessments able to quantify alcohol craving and identify specific craving pathways; genetic studies focused  C on specific polymorphisms associated with craving; and studies focused on the possible role of different neuroendocrine pathways in the neurobiology of alcohol craving. This review will focus on the role of neuroendocrinological pathways in alcohol craving and dependence. (2) Studies focused on the neuropharmacology of alcohol craving: these include studies testing different drugs working on neurotransmitters like dopamine, opioids, serotonin, GABA and others. This review will focus on the role of the GABAergic medication baclofen as a treatment for alcohol craving and dependence. The following review explores two distinct topics: (1) clinical studies that focus on the role of specific neuroendocrine pathways (i.e. appetitive peptides) will serve as an example of research where the primary goal is to investigate new pathways that can influence the mechanisms of alcohol craving; (2) clinical studies testing the role of the GABAergic baclofen in alcohol dependence will serve as an example of research where the primary goal is to investigate new medications that are potentially safe and effective in the treatment of alcohol dependence. UNDERSTANDING AND TREATING ALCOHOL CRAVING AND DEPENDENCE: RECENT NEUROENDOCRINOLOGICAL FINDINGS Evidence suggests that several neuroendocrine pathways may play a role in the mechanisms on the basis of alcohol craving and alcohol dependence. In particular, there is an increasing interest in the role of feeding-related pathways and their response in alcohol craving and dependence. In fact, research shows that The Author 2009. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved 342 Leggio alcohol and food-seeking behaviors share some common neural pathways (Li et al., 1987; Blum et al., 1996; Volkow et al., 2008; Addolorato et al., 2009). As a consequence, overlapping neuronal circuits exist between addiction and obesity (see Volkow et al., 2008). Therefore, neurobiological circuits related to the food-seeking behavior have been suggested as possible new targets in the treatment of alcohol dependence, such as the cannabinoid (CB; see Colombo et al., 2005) and the neuropeptide Y system (NPY; see Heilig and Thorsell, 2002). Consistent with these observations, there is converging research suggesting that feeding-regulating circuits may provide important information in understanding alcohol craving and dependence. These circuits involve peptides that are either orexigenic (e.g. ghrelin), anorexigenic (e.g. leptin, insulin, adiponectin) or both (e.g. thyroid hormones). These pathways are summarized in this review. Leptin Leptin is a neuropeptide secreted by white adipocytes. Leptin acts as a key regulator of food intake and energy expenditure, which plays an important role in hypothalamic appetite regulation (Inui, 1999). Leptin also regulates the hypothalamic– pituitary–a (...truncated)