Action of ethanol and zolpidem on gamma-aminobutyric acid responses from cerebellar Purkinje neurons: relationship to beta-adrenergic receptor input.

Givens and Breese1,2 reported that systemic administration of ethanol enhanced responses to GABA from some, but not all, medial septal neurons, while having no effect on responses from lateral septal neurons. Subsequently, Simson et al.3 reported that local application of ethanol had effects similar to those of systemically administered ethanol on GABA responses from medial septal neurons (i.e., ethanol enhanced some, but not all, responses to GABA). A follow-up report by Criswell et al.4 indicated ethanol enhanced responses to GABA from most, but not all, spontaneously active neurons in the substantia nigra reticulata, inferior colliculus, and ventral pallidum. In contrast to the positive action of ethanol to enhance GABA in the former brain regions, spontaneously active neurons in the lateral septum, ventral tegmental area, and the hippocampus were not sensitive to the action of ethanol to enhance GABA.4,5 During the course of these various investigations, it was noted that a high concentration of zolpidem binding was present in brain regions where neurons were found to be sensitive to ethanol enhancement of GABA, whereas zolpidem binding was low or virtually absent in brain regions where ethanol did not enhance responses to GABA.4–7 Therefore, the action of zolpidem and ethanol on GABA responses was tested on individual neurons in various regions of the brain 4,5 A positive relationship between the action of zolpidem and ethanol to enhance GABA-induced inhibition was found, providing support for the contention that the zolpidem-sensitive GABAA benzodiazepine (BZD) receptor would respond to ethanol enhancement of GABA.8 However, there were a few neurons encountered in the medial septum where this positive relationship between the actions of ethanol and zolpidem did not occur.8 In the survey of zolpidem binding in the brain, the cerebellar Purkinje layer contained a high concentration of zolpidem binding.6,7 Earlier work noted that only a relatively small population of cerebellar Purkinje neurons were sensitive to ethanol enhancement of GABA responses.9–12 In a portion of the Purkinje neurons insensitive to ethanol enhancement of GABA, Lin et al.9,10 reported that iontophoretic application of norepinephrine or isoproterenol allowed ethanol potentiation of GABA-induced inhibition from Purkinje neurons. Furthermore, application of a β-adrenergic antagonist to cerebellar Purkinje neurons initially sensitive to ethanol enhancement of GABA reduced this action of ethanol on GABA responsiveness.11,12 Based upon these previous data that cerebellar Purkinje neurons became sensitive to ethanol enhancement of GABA when a β-adrenergic agonist was added to the cell,9–12 the present investigation determined whether those cerebellar Purkinje neurons sensitive to β-adrenergic influences on ethanol action would be sensitive to zolpidem enhancement of responses to GABA. Thus, this approach was to provide information about the GABAA receptor subtype(s) on cerebellar Purkinje neurons initially sensitive or insensitive to ethanol enhancement of GABA. Given the variable response pattern reported for ethanol enhancement of responses to GABA from cerebellar Purkinje neurons,9,10 the present investigation initially tested the degree to which ethanol sensitivity of this cell type was related to the action of zolpidem to enhance responses to GABA. This investigation allowed an assessment of whether the action of zolpidem would be predictive of the action of ethanol on responses to GABA from cerebellar Purkinje neurons.