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

Neuropsychopharmacology. 2016 Mar;41(4):1112-27. doi: 10.1038/npp.2015.250. Epub 2015 Aug 9.


Alcoholism is associated with changes in brain reward and control systems, including the prefrontal cortex. In prefrontal areas, the orbitofrontal cortex (OFC) has been suggested to have an important role in the development of alcohol-abuse disorders and studies from this laboratory demonstrate that OFC-mediated behaviors are impaired in alcohol-dependent animals. However, it is not known whether chronic alcohol (ethanol) exposure alters the fundamental properties of OFC neurons. In this study, mice were exposed to repeated cycles of chronic intermittent ethanol (CIE) exposure to induce dependence and whole-cell patch-clamp electrophysiology was used to examine the effects of CIE treatment on lateral OFC (lOFC) neuron excitability, synaptic transmission, and plasticity. Repeated cycles of CIE exposure and withdrawal enhanced current-evoked action potential (AP) spiking and this was accompanied by a reduction in the after-hyperpolarization and a decrease in the functional activity of SK channels. CIE mice also showed an increase in the AMPA/NMDA ratio, and this was associated with an increase in GluA1/GluA2 AMPA receptor expression and a decrease in GluN2B NMDA receptor subunits. Following CIE treatment, lOFC neurons displayed a persistent long-term potentiation of glutamatergic synaptic transmission following a spike-timing-dependent protocol. Lastly, CIE treatment diminished the inhibitory effect of acute ethanol on AP spiking of lOFC neurons and reduced expression of the GlyT1 transporter. Taken together, these results suggest that chronic exposure to ethanol leads to enhanced intrinsic excitability and glutamatergic synaptic signaling of lOFC neurons. These alterations may contribute to the impairment of OFC-dependent behaviors in alcohol-dependent individuals.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Alcoholism / physiopathology*
  • Animals
  • Ethanol / administration & dosage*
  • Excitatory Postsynaptic Potentials / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity / drug effects*
  • Neurons / drug effects*
  • Neurons / physiology*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiology*
  • Protein Subunits / metabolism
  • Receptors, AMPA / physiology
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Small-Conductance Calcium-Activated Potassium Channels / physiology
  • Synaptic Transmission / drug effects


  • Protein Subunits
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Small-Conductance Calcium-Activated Potassium Channels
  • Ethanol