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

Abstract

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).

Effects of Varenicline on Ethanol‐Induced Conditioned Place Preference, Locomotor Stimulation, and Sensitization

“…Drugs that block the stimulant effects of ethanol and ethanol-induced sensitization in mice have also shown promise for the treatment of alcohol dependence in humans. For example, baclofen, a γ-aminobutyric acid (GABA)-B receptor agonist, which has shown promise for the treatment of alcohol dependence in some human studies and case reports (see Agabio and Colombo 2014; Leggio et al, 2010 for reviews) was also found to attenuate the stimulant effects of ethanol (Holstein et al, 2009) and ethanol-induced sensitization (Pastor et al, 2010) in mice. Our data suggest that activation of nAChR using a partial agonist may attenuate the locomotor effects of ethanol, which may be important to ethanol addiction.…”

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…Clinical and basic research indicate that alcohol abuse and dependence are mediated in part by a number of neurobiological systems (c.f., Koob, Arends, & Le Moal, 2014; Koob, Buck, et al, 2014; Noronha, Cui, Harris, & Crabbe, 2014; Pierce & Kenny, 2013; Robbins, Everitt, & Nutt, 2010; Self & Staley, 2010; Sommer & Spanagel, 2013; Spanagel, 2009): acetylcholine (ACh: Chatterjee & Bartlett, 2010; Davis & de Fiebre, 2006; Rahman, Engleman, & Bell, 2015, 2016; Soderpalm, Ericson, Olausson, Blomqvist, & Engel, 2000), adenosine (Filip, Zaniewska, Frankowska, Wydra, & Fuxe, 2012; Nam, Bruner, & Choi, 2013), dopamine (DA: Bhaskar & Kumar, 2014; Engel & Jerlhag, 2014; Heinz, 2002; Nutt, Lingfor-Hughes, Erritzoe, & Stokes, 2015; Soderpalm & Ericson, 2013), endocannabinoid (Moreira, Jupp, Belin, & Dalley, 2015), gamma-aminobutyric-acid (GABA: Agabio & Colombo, 2014; Kumar et al, 2009; Liang & Olsen, 2014; Maccioni & Colombo, 2009), glutamate (Barron et al, 2012; Bell et al, 2016; Davis & Wu, 2001; Gass & Olive, 2008; Rao, Bell, Engleman, & Sari, 2015), purinergic (Franklin et al, 2014), serotonin (5-HT: Engleman, Rodd, Bell, & Murphy, 2008; Hauser et al, 2014; Lovinger, 1999), melanocortin (Olney, Navarro, & Thiele, 2014), opiate (Charbogne, Kieffer, Befort, 2014; Drews & Zimmer, 1997), orexin (Baimel et al, 2015), oxytocin (Buisman-Pijlman et al, 2014), neuropeptide-Y (NPY: Heilig & Thorsell, 2002), corticotropin releasing factor (CRF: Burke & Miczek, 2014; Koob, 2010), substance P (George et al, 2008), nociceptin/orphanin FQ (NOP, N/OFQ: Economidou et al, 2008; Witkin et al, 2014); ghrelin (Jerlhag, Egecioglu, Dickson, & Engel, 2011; Jerlhag et al, 2009; Jerlhag, Landgren, et al, 2011); neurotrophic factors such as BDNF (Logrip, Janak, & Ron, 2009), and hypothalamic-pituitary-adrenal (HPA) activity including corticosteroids, etc. (Gianoulakis, Guillaume, De Waele, & Angelogianni, 1995; Keith, Roberts, Wisen, & Crabbe, 1995; Kiefer, Jahn, Otte, Nakovics, & Wiedemann, 2006…”

“…Acute alcohol experience potentiates GABA signaling and facilitates its hyperpolarizing actions (Koob, 2004). And, GABA A and GABA B receptors mediate some of the rewarding, reinforcing, and motivational effects of alcohol consumption and alcohol binge drinking (Eiler & June, 2007; Nowak, McBride, Lumeng, Li, & Murphy, 1998; Tanchuck, Yoneyama, Ford, Fretwell, & Finn, 2011; also see Agabio & Colombo, 2014). Systemically, the GABA A agonist topiramate (Breslin, Johnson, & Lynch, 2010; Lynch, Bond, Breslin, & Johnson, 2011) and GABA B agonist baclofen (Liang et al, 2006; Maccioni et al, 2012) and GABA B positive modulators GHB (June et al, 1995), CGP7930 (Liang et al, 2006) and GS39783 (Maccioni et al, 2012) all reduced ethanol drinking and/or self-administration by P rats.…”

High-dose baclofen for the treatment of alcohol dependence (BACLAD study): A randomized, placebo-controlled trial

“…The selective GABA-B receptor agonist baclofen is approved for the treatment of spasticity resulting from various neurological conditions. There is preclinical evidence from studies in rats that baclofen suppresses the acquisition and maintenance of alcohol drinking behavior as well as an increase in alcohol intake after a period of alcohol abstinence (Agabio and Colombo, 2014).…”