Does ethanol act preferentially via selected brain GABAA receptor subtypes? the current evidence is ambiguous

In rodent models, gamma-aminobutyric acid A (GABAA) receptors with the alpha6 and delta subunits, expressed in the cerebellar and cochlear nucleus granule cells, have been linked to ethanol sensitivity and voluntary ethanol drinking. Here, we review the findings. When considering both in vivo contributions and data on cloned receptors, the evidence for direct participation of the alpha6-containing receptors to increased ethanol sensitivity is poor. The alpha6 subunit-knockout mouse lines do not have any changed sensitivity to ethanol, although these mice do display increased benzodiazepine sensitivity. However, in general the compensations occurring in knockout mice (regardless of which particular gene is knocked out) tend to fog interpretations of drug actions at the systems level. For example, the alpha6 knockout mice have increased TASK-1 channel expression in their cerebellar granule cells, which could influence sensitivity to ethanol in the opposite direction to that obtained with the alpha6 knockouts. Indeed, TASK-1 knockout mice are more impaired than wild types in motor skills when given ethanol; this might explain why GABAA receptor alpha6 knockout mice have unchanged ethanol sensitivities. As an alternative to studying knockout mice, we examined the claimed delta subunit-dependent/gamma2 subunit-independent ethanol/[3H]Ro 15-4513 binding sites on GABAA receptors. We looked at [3H]Ro 15-4513 binding in HEK 293 cell membrane homogenates containing rat recombinant alpha6/4beta3delta receptors and in mouse brain sections. Specific high-affinity [3H]Ro 15-4513 binding could not be detected under any conditions to the recombinant receptors or to the cerebellar sections of gamma2(F77I) knockin mice, nor was this binding to brain sections of wild-type C57BL/6 inhibited by 1-100 mM ethanol. Since ethanol may act on many receptor and channel protein targets in neuronal membranes, we consider the alpha6 (and alpha4) subunit-containing GABAA receptors unlikely to be directly responsible for any major part of ethanol's actions. Therefore, we finish the review by discussing more generally alcohol and GABAA receptors and by suggesting potential future directions for this research.