Ethanol selectively attenuates NMDAR-mediated synaptic transmission in the prefrontal cortex.

Despite years of research and education about the adverse effects of excessive drinking, alcohol abuse and alcoholism remain leading causes of premature death and morbidity in the U.S. and other countries. Acutely, ethanol slows reaction time, leading to reduced motor control, and impairs perception and judgment regarding the outcome of potentially risky behaviors. Deficits in cognitive processing and higher order functions may persist in individuals that are alcohol-dependent or those who have undergone multiple cycles of dependence and withdrawal. These changes have been documented by brain imaging and behavioral studies and suggest that areas of the prefrontal cortex (PFC) in particular may be especially susceptible to alcohol-induced damage (for review, see Moselhy et al., 2001). Reduced prefrontal function following long-term alcohol use may contribute to the loss of control over drinking that is a hallmark of alcoholism (Goldman-Rakic, 1999; Kalivas et al., 2005). While imaging and behavioral studies have identified the PFC as an ethanol-sensitive brain region, relatively little is known regarding the mechanisms by which these changes take place. Among the various ethanol-sensitive cellular processes that have been investigated to date, the large family of ligand-gated ion channels appears to be a particularly relevant target for many of the acute actions of ethanol. Several reports have demonstrated that ion flux through both native and recombinant channels gated by various neurotransmitters is altered by concentrations of ethanol associated with behavioral signs of intoxication. Most of these studies have focused on brain regions associated with reward or learning and memory pathways and have identified alcohol sensitive conductances in regions such as the nucleus accumbens (Nie et al., 1994), hippocampus (Lovinger et al., 1990), and amygdala (Roberto et al., 2004). The PFC, which exerts modulatory control over many of these regions, has received relatively little attention as an important site of action for alcohol. In a recent study from this laboratory, we reported that ethanol inhibited persistent network activity in the PFC both in vivo and in a novel slice culture system (Tu et al., 2007). Persistent activity is characterized by spontaneous membrane depolarizations, termed “up-states”, that are driven by synaptic activity. These “up-states” involve both glutamatergic and GABAergic ion channels that have previously been shown to be sensitive to behaviorally relevant concentrations of ethanol (Seamans et al., 2003). Ethanol was shown to reduce both the amplitude and duration of up-states in PFC neurons, suggesting that conductances that underlie the onset and duration of up-states are sensitive to ethanol (Tu et al., 2007). In the present study, we examined the effects of ethanol on pharmacologically isolated glutamatergic and GABAergic responses in acutely dissected slices of rat PFC. The results of these studies reveal that N-methyl d-aspartate-type glutamate receptor (NMDAR)-mediated events appear especially sensitive to ethanol while those generated by α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid-type glutamate receptor (AMPARs) or a-type γ-aminobutyric acid receptor (GABAARs) are relatively resistant. These findings provide additional evidence to support the hypothesis that the PFC is an important target for the actions of ethanol.