Chronic caffeine exposure in rats results in tolerance and sensitization to local brain oxygenation post seizures in a sex dependent fashion

Abstract Postictal hypoxia, which follows a seizure, occurs in part due to vasoconstriction and contributes to several short- and longer-term consequences that can significantly impair an individual’s well-being. When administered before a seizure, caffeine has been shown to extend the postictal hypoxic period significantly in male rats. Given that much of the world’s population consumes it daily, the long-term effects of caffeine administration on postictal hypoxia warrant further investigation. Here, we focus on the acute and chronic effects of caffeine on hippocampal oxygen levels before and after seizures in both female and male young adult Long-Evans rats. In caffeine-naïve rats, acute caffeine lowered brain oxygen levels and increased the severity and duration of postictal hypoxia similarly in both sexes. In caffeine-experienced rats, acute caffeine yielded similar results, but females showed less severity and duration of postictal hypoxia. Caffeine-experienced males also showed less severity of postictal hypoxia relative to their naïve state, but not its duration or faster recovery. Over the 4-week chronic ad libitum caffeine exposure females during the postictal period displayed faster time to recover from severe hypoxia indicating the development of tolerance whilst the males displayed the opposite effect of longer times to recover from severe hypoxia indicating sensitization. These results reveal that in response to chronic caffeine, sex-specific tolerance or sensitization develops differently across measures of postictal hypoxia. Our findings emphasize the need for further research on the effects of caffeine intake in women and men with epilepsy to reduce the risk of exacerbating postictal hypoxia and its associated comorbidities.