Tolerance to Alcohol‐Stimulated Glutamate Receptor Phosphorylation in the Central Amygdala and Prefrontal Cortex after Chronic Nicotine Exposure

Abstract

Nicotine and alcohol are two of the most commonly abused substances. 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. Mechanisms underlying these interactions are largely unknown, and there is little information on neuronal signaling events that occur in animals exposed to both drugs. In the present experiment, adult male Wistar rats were exposed to room air (non‐dependent group) or intermittent nicotine vapor (nicotine‐dependent group) for 12 hours per day (resulting in 12 hours of withdrawal per day) for three weeks. This treatment regimen has been shown to produce symptoms of nicotine dependence as evidenced by hyperalgesia and elevated nicotine self‐administration during withdrawal. On the final day of nicotine exposure, at 10 hours of withdrawal, animals were challenged with either saline or alcohol (1 g/kg, IP) and euthanized 15 minutes later. Brains were snap frozen and dissected for processing via Western analysis. We examined changes in the phosphorylation status of glutamate receptor subunits in stress‐ and reward‐related brain regions since excitatory neuroadaptations are heavily implicated in both alcohol and nicotine addiction. We discovered differential alterations in glutamate receptor subunit phosphorylation following nicotine withdrawal and alcohol challenge. For example, alcohol significantly increased PKA phosphorylation of GluR1 (a subunit of the AMPA receptor) across multiple brain regions, including the hippocampus, dorsomedial prefrontal cortex (dmPFC), and central amygdala (CeA). However, this neuroadaptation was largely absent in the dmPFC and CeA in animals exposed to chronic intermittent nicotine vapor (significant interaction between alcohol challenge and nicotine exposure). These data suggest a molecular tolerance to alcohol‐stimulated phosphorylation of GluR1 (a subunit of the AMPA receptor) in these regions in the context of nicotine dependence. As a consequence, more alcohol may be required to influence glutamatergic plasticity in the nicotine‐dependent state, and this may in part mediate increased drinking in heavy smokers.Support or Funding InformationOur research is supported by the following grants from the National Institute on Alcohol Abuse and Alcoholism: R01AA023305 (NWG) R00AA020839 (SE) T32AA007577 (MAM)