Individual differences in brain cocaine pharmacokinetics predict cocaine intake patterns in rats

Pharmacokinetic factors play a critical role in cocaine use. Previous work mainly examined externally driven pharmacokinetic manipulations, showing that conditions producing rapid fluctuations in brain cocaine levels, such as intermittent versus continuous access, promote burst-like intake, increased motivation for cocaine, heightened relapse vulnerability, and persistent drug-seeking behavior. Importantly, even under identical access conditions, substantial inter-individual variability exists in both the amount and speed of cocaine self-administration. In contrast to access-related pharmacokinetic influences, the contribution of intrinsic pharmacokinetic factors remains largely unexplored. To address this gap, male rats self-administered cocaine (0.8 mg/kg/injection; maximum 35 injections/session) for up to 26 sessions. In a final session, all animals received eight non-contingent intravenous cocaine injections at 5-min intervals before brain collection. Cocaine and its metabolites (ecgonine methyl ester, benzoylecgonine, norcocaine) were quantified in eleven sampled brain regions using liquid chromatography-tandem mass spectrometry detection and related to previous self-administration behavior. Mean brain cocaine concentration matched predictions from a widely used pharmacokinetic model, yet marked inter-individual variability was observed. Lower cocaine levels and higher metabolite-to-cocaine ratios were associated with faster self-administration patterns, but not with the total amount of cocaine previously consumed. This suggests that the observed inter-individual pharmacokinetic variability is unlikely to result from differential metabolic adaptations driven by intake and may contribute to differences in cocaine intake patterns. Overall, inter-individual variability in cocaine pharmacokinetics in the rat exist and are related to differences in cocaine intake patterns, with rapid intake representing a known risk factor for problematic cocaine use in both rodents and humans.