Chronic EtOH effects on putative measures of compulsive behavior in mice

Addict Biol. 2017 Mar;22(2):423-434. doi: 10.1111/adb.12342. Epub 2015 Dec 21.


Addictions, including alcohol use disorders, are characterized by the loss of control over drug seeking and consumption, but the neural circuits and signaling mechanisms responsible for the transition from controlled use to uncontrolled abuse remain incompletely understood. Prior studies have shown that 'compulsive-like' behaviors in rodents, for example, persistent responding for ethanol (EtOH) despite punishment, are increased after chronic exposure to EtOH. The main goal of the current study was to assess the effects of chronic intermittent EtOH (CIE) exposure on multiple, putative measures of compulsive-like EtOH seeking in C57BL/6 J mice. Mice were exposed to two or four weekly cycles of CIE and then, post-withdrawal, tested for progressive ratio responding for EtOH, sustained responding during signaled EtOH unavailability and (footshock) punished suppression of responding for EtOH. Results showed that mice exposed to CIE exhibited attenuated suppression of EtOH seeking during punishment, as compared with air-exposed controls. By contrast, CIE exposure affected neither punished food reward-seeking behavior, nor other putative measures of compulsive-like EtOH seeking. Ex vivo reverse transcription polymerase chain reaction analysis of brain tissue found reduced sensitivity to punished EtOH seeking after CIE exposure was accompanied by a significant increase in gene expression of the GluN1 and GluN2A subunits of the N-methyl-d-aspartate receptor, specifically in the medial orbitofrontal cortex. Moreover, slice electrophysiological analysis revealed increased N-methyl-d-aspartate receptor-mediated currents in the orbitofrontal cortex after CIE exposure in test-naïve mice. Collectively, the current findings add to the growing body of evidence demonstrating that chronic exposure to EtOH fosters resistance to punished EtOH seeking in association with adaptations in cortical glutamatergic transmission.

Keywords: Addiction; CIE; NMDAR; alcohol; mouse; orbitofrontal cortex.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Central Nervous System Depressants / administration & dosage
  • Central Nervous System Depressants / pharmacology*
  • Compulsive Behavior* / genetics
  • Drug-Seeking Behavior / drug effects*
  • Ethanol / administration & dosage
  • Ethanol / pharmacology*
  • Food
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / genetics
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Punishment*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Reward


  • Central Nervous System Depressants
  • Gprin1 protein, mouse
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Ethanol
  • N-methyl D-aspartate receptor subtype 2A