Physiology and pharmacology of alcohol: the imidazobenzodiazepine alcohol antagonist site on subtypes of GABA_A receptors as an opportunity for drug development?

Abstract

Alcohol (ethanol, EtOH) has pleiotropic actions and induces a number of acute and long-term effects due to direct actions on alcohol targets, and effects of alcohol metabolites and metabolism. Many detrimental health consequences are due to EtOH metabolism and metabolites, in particular acetaldehyde, whose high reactivity leads to nonspecific chemical modifications of proteins and nucleic acids. Like acetaldehyde, alcohol has been widely considered a nonspecific drug, despite rather persuasive evidence implicating inhibitory GABA A receptors (GABA A Rs) in acute alcohol actions, for example, a GABA A R ligand, the imidazobenzodiazepine Ro15-4513 antagonizes many low-to-moderate dose alcohol actions in mammals. It was therefore rather surprising that abundant types of synaptic GABA A Rs are generally not responsive to relevant low concentrations of EtOH. In contrast, d-subunit-containing GABA A Rs and extrasynaptic tonic GABA currents mediated by these receptors are sensitive to alcohol concentrations that are reached in blood and tissues during low-to-moderate alcohol consumption. We recently showed that low-dose alcohol enhancement on highly alcohol-sensitive GABA A R subtypes is antagonized by Ro15-4513 in an apparently competitive manner, providing a molecular explanation for behavioural Ro15-4513 alcohol antagonism. The identification of a Ro15-4513/EtOH binding site on unique GABA A R subtypes opens the possibility to characterize this alcohol site(s) and screen for compounds that modulate the function of EtOH/Ro15-4513-sensitive GABA A Rs. The utility of such drugs might range from novel alcohol antagonists that might be useful in the emergency room, to drugs for the treatment of alcoholism, as well as alcohol-mimetic drugs to harness acute positive effects of alcohol.

Antagonism of the Ethanol-Like Discriminative Stimulus Effects of Ethanol, Pentobarbital, and Midazolam in Cynomolgus Monkeys Reveals Involvement of Specific GABAAReceptor Subtypes

“…Flumazenil and Ro15-4513 act at common GABA A receptor subtypes as flumazenil blocks antagonism by Ro15-4513 (Suzdak et al, 1986) and displaces Ro15-4513 binding at ␣ 4 ␤ 3 ␦ receptors (Wallner and Olsen, 2008). Studies in recombinant receptor expression systems suggest that flumazenil has very low affinity for "benzodiazepine-insensitive" GABA A receptors containing ␣ 4 and ␣ 6 subunits (K i ϭ 90 -107 nM), but equal affinity for "benzodiazepine-sensitive" GABA A receptors containing ␣ 1 , ␣ 2 , ␣ 3 , or ␣ 5 subunits (K i ϭ 0.40 -1.5 nM).…”

Alcohol- and Alcohol Antagonist-Sensitive Human GABAA Receptors: Tracking δ Subunit Incorporation into Functional Receptors

“…In addition, ethanol enhancement of ␦ subunit-containing re-ceptors is competitively antagonized by the rat behavioral alcohol antagonist 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid ethyl ester (Ro15-4513) (Hanchar et al, 2006;Wallner et al, 2006b). These results provided evidence that EtOH/Ro15-4513-sensitive GABA A R subtypes mediate behaviorally relevant alcohol effects in mammals and provide a detailed molecular explanation for the efficacy of the imidiazobenzodiazepine Ro15-4513 as an alcohol antagonist (Suzdak et al, 1986;Wallner et al, 2006b;Wallner and Olsen, 2008). It is noteworthy that the extrasynaptic GABA A R hypothesis has been extensively corroborated by recordings from ␦ subunit-containing native neurons (Wei et al, 2004;Hanchar et al, 2005;Fleming et al, 2007;Glykys et al, 2007;Liang et al, 2007;Santhakumar et al, 2007;Jia et al, 2008).…”

Complementary and alternative medicine: Herbals and supplements: A review for the primary care physician

“…The relationship of chronic alcohol intake to cirrhosis is well-recognized [83]. Alcohol metabolism produces acetaldehyde, which results in nonspecific modification of nucleic acids and proteins [84]. Alcohol consumption along with use of tobacco and betel chewing is associated with increased oral cancer risk [85]; alcohol intake is a risk factor for pancreatitis and pancreatic cancer, especially in the presence of additional risk factors, such as amount and duration of use, heredity, autoimmune factors, and smoking.…”