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

Neuropsychopharmacology. 2013 Jun;38(7):1176-88. doi: 10.1038/npp.2013.12. Epub 2013 Jan 11.

Abstract

Trauma-induced damage to the orbitofrontal cortex (OFC) often results in behavioral inflexibility and impaired judgment. Human alcoholics exhibit similar cognitive deficits suggesting that OFC neurons are susceptible to alcohol-induced dysfunction. A previous study from this laboratory examined OFC mediated cognitive behaviors in mice and showed that behavioral flexibility during a reversal learning discrimination task was reduced in alcohol-dependent mice. Despite these intriguing findings, the actions of alcohol on OFC neuron function are unknown. To address this issue, slices containing the lateral OFC (lOFC) were prepared from adult C57BL/6J mice and whole-cell patch clamp electrophysiology was used to characterize the effects of ethanol (EtOH) on neuronal function. EtOH (66 mM) had no effect on AMPA-mediated EPSCs but decreased those mediated by NMDA receptors. EtOH (11-66 mM) also decreased current-evoked spike firing and this was accompanied by a decrease in input resistance and a modest hyperpolarization. EtOH inhibition of spike firing was prevented by the GABAA antagonist picrotoxin, but EtOH had no effect on evoked or spontaneous GABA IPSCs. EtOH increased the holding current of voltage-clamped neurons and this action was blocked by picrotoxin but not the more selective GABAA antagonist biccuculine. The glycine receptor antagonist strychnine also prevented EtOH's effect on holding current and spike firing, and western blotting revealed the presence of glycine receptors in lOFC. Overall, these results suggest that acutely, EtOH may reduce lOFC function via a glycine receptor dependent process and this may trigger neuroadaptive mechanisms that contribute to the impairment of OFC-dependent behaviors in alcohol-dependent subjects.

Publication types

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

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Bicuculline / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Ethanol / antagonists & inhibitors
  • Ethanol / pharmacology*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • GABA Antagonists / pharmacology
  • Glycine Agents / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Neurons / drug effects*
  • Neurons / physiology*
  • Picrotoxin / pharmacology
  • Prefrontal Cortex / cytology*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiology
  • Receptors, AMPA / drug effects
  • Receptors, Glycine / metabolism*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Strychnine / pharmacology

Substances

  • GABA Antagonists
  • Glycine Agents
  • Receptors, AMPA
  • Receptors, Glycine
  • Receptors, N-Methyl-D-Aspartate
  • Picrotoxin
  • Ethanol
  • Strychnine
  • Bicuculline