Actions of Acute and Chronic Ethanol on Orbitofrontal Cortex Neurons

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Woodward JJ1
1Dept. of Neuroscience, Medical Univ. of South Carolina, Charleston, SC, USA

The effects of alcohol on neurons and behaviors associated with key brain reward systems have been well documented while those on frontal cortical areas including the orbitofrontal cortex (OFC) are less well known. Using a mouse model of alcohol dependence, we have carried out a series of behavioral and slice electrophysiological studies to address this gap in our understanding. When applied acutely to OFC slices from adult mice, ethanol (22-66 mM) has little effect on inhibitory GABA-mediated IPSCs or excitatory AMPA-mediated EPSCs while those mediated by NMDA receptors are modestly inhibited at the higher concentrations. In contrast, low concentrations of ethanol (~11 mM) inhibit current-evoked spiking and this effect requires strychnine-sensitive glycine receptors. In post-withdrawal, alcohol-dependent mice, OFC spiking is dramatically enhanced and this is accompanied by a significant loss of apamin-sensitive current that underlies the medium after-hyperpolarization. Neurons from these mice also show a blunting of both ethanol and glycine mediated inhibition of firing, increases in the AMPA/NMDA ratio and enhanced long-term potentiation following a spike-timing protocol. Data from recent studies shows that in ethanol-naïve mice, OFC spiking is reduced by activation of Gi/o coupled receptors including dopamine D2, norepinephrine a2, serotonin 5HT1A and GABAB. The direct acting GIRK channel agonist ML297 also inhibits firing and neurotransmitter-dependent inhibition is blocked by the GIRK channel antagonist barium. In post-withdrawal, alcohol-dependent mice, inhibition of firing by neurotransmitters and ML297 is lost with no apparent change in expression of GIRK channels or Gi/o proteins. Interestingly, the recovery modulation of spiking by ML297 occurs before that for neurotransmitters suggesting multiple mechanisms of action. Behavioral studies show that alcohol-dependent mice have deficits in the reversal learning phase of a naturalistic food foraging task previously demonstrated to be OFC-dependent. In addition, excitotoxic lesions or chemogenetic inhibition of the lateral OFC have no effect on ethanol consumption in non-dependent mice but elevate the already enhanced drinking seen in dependent mice. Overall, these findings establish the OFC as a critical target for ethanol and suggest that deficits in OFC function may underlie various behavioral outcomes associated with alcohol dependence. Supported by AA009986 and AA10761.

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