Withdrawal from Chronic Nicotine Exposure Produces Region-Specific Tolerance to Alcohol-Stimulated GluA1 Phosphorylation

Alcohol Clin Exp Res. 2016 Dec;40(12):2537-2547. doi: 10.1111/acer.13258. Epub 2016 Oct 31.


Background: Nicotine use increases alcohol drinking, suggesting that the combination of these drugs may produce synergistic effects in activating reward circuitry. Alternatively, use of either of these drugs may facilitate the development of cross-tolerance to the other to promote intake escalation.

Methods: In this study, adult male Wistar rats were chronically exposed to room air or chronic, intermittent nicotine vapor, which has been shown to produce symptoms of nicotine dependence as evidenced by elevated nicotine self-administration and a host of somatic and motivational withdrawal symptoms. We examined regional neuroadaptations in nicotine-experienced versus nonexperienced animals, focusing on changes in phosphorylation of the AMPA glutamate channel subunit GluA1 in reward-related brain regions as excitatory neuroadaptations are heavily implicated in both alcohol and nicotine addiction.

Results: During withdrawal, nicotine exposure and alcohol challenge (1 g/kg) interactively produced neuroadaptations in GluA1 phosphorylation in a brain region-dependent manner. Alcohol robustly increased protein kinase A-mediated phosphorylation of GluA1 at serine 845 in multiple regions. However, this neuroadaptation was largely absent in 3 areas (dorsomedial prefrontal cortex, dorsal striatum, and central amygdala) in nicotine-experienced animals. This interactive effect suggests a molecular tolerance to alcohol-stimulated phosphorylation of GluA1 in the context of nicotine dependence.

Conclusions: Nicotine may modify the rewarding or reinforcing effects of alcohol by altering glutamate signaling in a region-specific manner, thereby leading to increased drinking in heavy smokers.

Keywords: Alcohol; Amygdala; Glutamate; Nicotine; Prefrontal Cortex.

MeSH terms

  • Administration, Inhalation
  • Animals
  • Brain / metabolism
  • Drug Interactions
  • Drug Tolerance*
  • Ethanol / pharmacology*
  • Male
  • Nicotine / administration & dosage
  • Nicotine / adverse effects*
  • Phosphorylation / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, AMPA / metabolism*
  • Substance Withdrawal Syndrome / metabolism*


  • Receptors, AMPA
  • Ethanol
  • Nicotine
  • glutamate receptor ionotropic, AMPA 1