Similar adenosine neuromodulation in male and female hippocampal and prefrontocortical synapses of young and aged mice

Caffeine is the most widely consumed psychoactive drug worldwide, acting through adenosine receptors at non-toxic doses. Epidemiological studies have reported a different impact of caffeine in men and women, namely in the incidence of brain stroke and neurodegenerative diseases. This prompts the tentative hypothesis that adenosine neuromodulation might be different in males and females, which we now tested. In hippocampal slices from adult mice, the potency and efficacy of 2-chloroadenosine to inhibit synaptic transmission and the disinhibitory effect resulting from selective blockade of adenosine A₁ receptors, were superimposable in males and females. Likewise, a similar adenosine neuromodulation was observed in synapses of the hippocampus and prefrontal cortex of aged male and female mice. This excludes the possibility that differences in A₁ receptor function contribute to the sex-specific central effects of caffeine, which may arise from variations in metabolism, interactions with sex hormones, or differences in brain connectivity—factors that remain to be investigated.