Little Evidence of a Role for the α1GABA_A Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

Abstract

Background Alcohol potentiates GABAergic neurotransmission via action at the GABAA receptor. α1 subunit-containing GABAA receptors have been implicated as mediators, in part, of the behavioral and abuse-related effects of alcohol in rodents. Methods We systematically investigated the effects of one α1-preferring benzodiazepine agonist, zolpidem, and two antagonists, βCCT and 3-PBC, on oral self-administration of alcohol (2% w/v) or sucrose solution and observable behavior in rhesus macaques. We compared these effects to those of the nonselective benzodiazepine agonist triazolam, antagonist flumazenil, and inverse agonist βCCE. Results Alcohol and sucrose solutions maintained reliable baseline drinking behavior across the study. The α1-preferring compounds did not affect intake, number of sipper extensions, or blood alcohol levels at any of the doses tested. Zolpidem, βCCT, and 3-PBC increased latency to first sipper extension in animals self-administering alcohol, but not sucrose, solution. Triazolam exerted biphasic effects on alcohol drinking behavior, increasing intake at low doses but decreasing BAL and increasing latency at higher doses. At doses higher than those effective in alcohol-drinking animals, triazolam increased sucrose intake and latency. Flumazenil non-systematically increased number of extensions for alcohol but decreased BAL, with no effects on sucrose drinking. βCCE decreased sipper extensions for alcohol and increased latency for first sucrose sipper extension, but full dose-effect relationships could not be determined due to seizures at higher doses. Conclusions Alcohol-drinking animals appeared more sensitive to the effects of GABAergic compounds on drinking behavior. However, these results do not support a strong contribution of α1GABA receptors to the reinforcing effects of alcohol in primates.

Reinforcing effectiveness of midazolam, ethanol, and sucrose: behavioral economic comparison of a mixture relative to its component solutions

“…Given the abuse liability of BZ and ethanol as individual reinforcers, it seems reasonable to assume that a major determinant of co-administration of these two drugs is related to their reinforcing effects. However, the equivocal findings of the aforementioned investigations of this topic (i.e., Barrett and Weinberg, 1975; Chan et al 1983a,b; Petry, 1995, 1997; Roehrs et al, 1984; Samson and Grant, 1985; Sawyer et al, 2014; Soderpalm and Hansen, 1998; Winger et al, 2007; current report) suggest that there may be little, if any, reliable enhancement of reinforcing effects when co-administering these drugs. One possibility is that BZ and ethanol co-administration is partially attributable to misuse of the medication, as opposed to recreational abuse.…”

“…However, investigations of this possibility have yielded seemingly equivocal findings, at least in terms of ethanol consumption. For instance, studies have reported that BZ treatment increases (Petry, 1995; Petry, 1997; Sawyer et al, 2014; Schmitt et al, 2002; Soderpalm and Hansen, 1998; Winger et al, 2007), decreases (Chan et al, 1983a,b; Roehrs et al, 1984; Samson and Grant, 1985), or has no effect (Barrett and Weinberg, 1975; Leonard et al, 2006; Rimondini et al, 2002; Roehrs et al, 1984) on measures of ethanol consumption. However, the reinforcing effects of the BZ in isolation were only assessed in the study of Winger et al (2007), so the other reports were unable to compare the relative reinforcing effects of the mixture to that of each of its components (i.e., both the BZ and ethanol).…”

Effects of the benzodiazepine GABAA α1-preferring antagonist 3-isopropoxy-β-carboline hydrochloride (3-ISOPBC) on alcohol seeking and self-administration in baboons

“…In baboons, 3-PBC reduced self-administration of alcohol but also had some effects on self-administration of a non-alcoholic reinforcer (Kaminski et al, 2013). In contrast to the findings in rodents and baboons, both 3-PBC and βCCT failed to attenuate alcohol drinking in rhesus macaques (Sawyer et al, 2014). The reason for this contradictory result is unclear; however, the highest dose of 3-PBC tested in Sawyer et al's study (10.0 mg/kg) was lower than that which reduced total g/kg alcohol intake in the baboon model (18.0 mg/kg).…”

“…In primates, chronic administration of 3-PBC significantly decreased self-administration responses, volume consumed, and g/kg alcohol intake but also had some effects on self-administration of a non-alcoholic reinforcer in one study (Kaminski et al, 2013). In another study, chronic administration of 3-PBC and βCCT did not decrease alcohol intake or blood alcohol levels (Sawyer et al, 2014). …”

Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

“…18, 24, 25 Behavioral studies in several species (e.g., rats, mice, primates) show that these ligands were BDZ antagonists, at the α1 Bz/GABA A subtype exhibiting competitive binding-site interactions with BDZ agonists over a broad range of doses. 18, 24, 26 In studies which involved the α1 subtype, they were shown to selectively reduce alcohol-motivated behaviors and more importantly, 3-PBC·HCl significantly reduced alcohol self-administration and reduced craving in baboons. 26 β-Carbolines 1·HCl and 3 displayed mixed weak agonist-antagonist profiles in vivo in alcohol preferring (P) and high alcohol drinking (HAD) rats.…”