Abstract
In many rodent brain regions, alcohol increases vesicular release of GABA, resulting in an increase in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and the magnitude of tonic GABAA receptor (GABAAR) currents. A neglected issue in translating the rodent literature to humans is the possibility that phylogenetic differences alter the actions of alcohol. To address this issue we made voltage-clamp recordings from granule cells (GCs) in cerebellar slices from the non-human primate (NHP), Macaca fascicularis. We found that similar to Sprague Dawley rats (SDRs), NHP GCs exhibit a tonic conductance generated by α6δ subunit containing GABAARs, as evidenced by its blockade by the broad spectrum GABAAR antagonist, GABAzine (10 μM), inhibition by α6 selective antagonist, furosemide (100 μM), and enhancement by THDOC (10–20 nM) and THIP (500 nM). In contrast to SDR GCs, in most NHP GCs (~60%), application of EtOH (25–105 mM) did not increase sIPSC frequency or the tonic GABAAR current. In a minority of cells (~40%), EtOH did increase sIPSC frequency and the tonic current. The relative lack of response to EtOH was associated with reduced expression of neuronal nitric oxide synthase (nNOS), which we recently reported mediates EtOH-induced enhancement of vesicular GABA release in rats. The EtOH-induced increase in tonic GABAAR current was significantly smaller in NHPs than in SDRs, presumably due to less GABA release, because there were no obvious differences in the density of GABAARs or GABA transporters between SDR and NHP GCs. Thus, EtOH does not directly modulate α6δ subunit GABAARs in NHPs. Instead, EtOH enhanced GABAergic transmission is mediated by enhanced GABA release. Further, SDR GC responses to alcohol are only representative of a subpopulation of NHP GCs. This suggests that the impact of EtOH on NHP cerebellar physiology will be reduced compared to SDRs, and will likely have different computational and behavioral consequences.
Highlights
Alcohol abuse is a leading cause of preventable death and illness, and the economic cost of alcohol abuse, including treatment and healthcare, lost productivity and various adverse social impacts is estimated to be $185 billion annually in the USA alone (Harwood, 2000)
Recent studies with Sprague Dawley rat (SDR) brain slice preparations have determined that a dominant mechanism by which alcohol (EtOH) enhances GABAergic transmission is via enhanced vesicular release of GABA, with a resultant increase in the frequency of GABAA receptor (GABAAR)-mediated spontaneous inhibitory postsynaptic currents (Roberto et al, 2003; Criswell et al, 2008; Theile et al, 2008)
Similar to what we and others have reported for SDR granule cells (GCs) (Brickley et al, 1996; Wall and Usowicz, 1997; Hamann et al, 2002a), non-human primate (NHP) GCs exhibited tonic GABAAR currents with superimposed phasic GABAARmediated spontaneous inhibitory postsynaptic currents (sIPSCs), both of which were blocked by the broad spectrum GABAAR antagonist, GABAzine (10 μM; Figure 1A)
Summary
Alcohol abuse is a leading cause of preventable death and illness, and the economic cost of alcohol abuse, including treatment and healthcare, lost productivity and various adverse social impacts is estimated to be $185 billion annually in the USA alone (Harwood, 2000). Recent studies with Sprague Dawley rat (SDR) brain slice preparations have determined that a dominant mechanism by which alcohol (EtOH) enhances GABAergic transmission is via enhanced vesicular release of GABA, with a resultant increase in the frequency of GABAA receptor (GABAAR)-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) (Roberto et al, 2003; Criswell et al, 2008; Theile et al, 2008). The EtOH-induced vesicular GABA release can increase the magnitude of tonic GABAAR currents in cell types that express the specialized class of extrasynaptic GABAARs that generate tonic GABAAR currents (Carta et al, 2004; Hanchar et al, 2005). It is being debated whether the EtOH-induced increase in tonic GABAAR current is due to the increased vesicular release of GABA and consequent increase in ambient concentrations, or whether there is a direct potentiation of the GABAAR subunits that mediate tonic currents (Hanchar et al, 2005; Borghese et al, 2006; Borghese and Harris, 2007; Botta et al, 2007a,b; Korpi et al, 2007; Santhakumar et al, 2007)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
