Effects of chronic intermittent ethanol exposure on orbitofrontal and medial prefrontal cortex-dependent behaviors in mice.

Abstract

In humans, stroke or trauma-induced damage to the orbitofrontal cortex (OFC) or medial prefrontal cortex (mPFC) results in impaired cognitive flexibility. Alcoholics also exhibit similar deficits in cognitive flexibility suggesting that the OFC and mPFC are susceptible to alcohol-induced dysfunction. The present experiments investigated this issue using an attention set-shifting assay in ethanol dependent adult male C57BL/6J mice. Ethanol dependence was induced by exposing mice to repeated cycles of chronic intermittent ethanol (CIE) vapor inhalation. Behavioral testing was conducted 72 hours or 10 days following CIE exposure to determine whether ethanol-induced changes in OFC-dependent (reversal learning) and mPFC-dependent (set-shifting) behaviors are long-lasting. During early ethanol abstinence (72 hrs), CIE mice showed reduced reversal learning performance as compared to controls. Reversal learning deficits were revealed as greater number of trials to criterion, more errors made and a greater difficulty in performing a reversal learning task relative to baseline performance. Furthermore, the magnitude of the impairment was greater during reversal of a simple discrimination rather than reversal of an intradimensional shift. Reversal learning deficits were no longer present when mice were tested 10 days after CIE exposure suggesting that ethanol-induced changes in OFC function can recover. Unexpectedly, performance on the set-shifting task was not impaired during abstinence from ethanol. These data suggest reversal learning, but not attention set-shifting, is transiently disrupted during short-term abstinence from CIE. Given that reversal learning requires an intact OFC, these findings support the idea that the OFC may be vulnerable to the cognitive impairing actions of ethanol.

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…Acute exposure to ethanol disrupts reversal learning in monkeys (Jedema et al, 2011) and rats (Brown et al, 2007), and suppresses electrophysiological activity of lOFC neurons in mice (Badanich et al, 2013). Previous studies in our laboratory also demonstrate that mice exposed chronically to ethanol show impaired performance on a reversal learning task (Badanich et al, 2011) shown to require the lOFC (Bissonette et al, 2008). These findings are similar to those reported in human alcoholics (Fortier et al, 2008(Fortier et al, , 2009Verdejo-Garcia et al, 2006), suggesting that alcohol-induced changes in OFC function may lead to loss of behavioral flexibility and poor judgment.…”

“…Although not yet completely understood, these dynamic changes in PFC/OFC neuronal function may contribute to the alterations in OFC-and PFC-based behaviors (eg, reversal learning and set-shifting) that are observed during post-WD periods similar to those examined in this study (Badanich et al, 2011;DePoy et al, 2013;Holmes et al, 2012;Kroener et al, 2012;Trantham-Davidson et al, 2014). Such changes, if present in alcohol-dependent humans, may contribute to cognitive and behavioral deficits associated with long-term alcohol abuse that underlie the inability of these individuals to exert cognitive control over their drinking in the face of adverse consequences.…”

“…Chronic intermittent ethanol (CIE) exposure of mice was initiated using a protocol previously shown to produce an impairment of OFC-dependent reversal learning (Badanich et al, 2011). Briefly, mice were exposed to four cycles of either ethanol (CIE group) or air (control) in vapor inhalation chambers.…”

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

“…Chronic alcohol exposure has also been shown to disrupt behavioral flexibility in experimental models of alcohol dependence. In a previous study from this lab, (Badanich et al, 2011), alcohol-dependent mice showed impaired performance on a reversal learning task that requires an intact OFC (Bissonette et al, 2008). Together with reports from human alcoholics, these findings suggest that OFC neurons may be particularly sensitive to alcohol.…”

“…EtOH's effect on OFC neuron excitability was only slightly dose-dependent as all three concentrations tested (11, 33, 66 mM) had similar effects on spike frequency and input resistance. These values span the range of blood EtOH concentrations found in humans following light (0.05% BEC) to heavy (0.31% BEC) drinking and encompass those produced in alcoholdependent mice (B0.18-0.225%; 40-50 mM) that, following withdrawal, express deficits in OFC-mediated cognitive flexibility (Badanich et al, 2011). Reports of EtOH affecting current-induced spike firing of neurons in other brain areas are mixed with some studies showing effects similar to the present study and others showing no effect.…”