Individual differences in brain cocaine pharmacokinetics predict cocaine intake patterns in rats
Abstract
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.
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BibTeX
@article{conlisk2026individual,
title = {{Individual differences in brain cocaine pharmacokinetics predict cocaine intake patterns in rats}},
author = {Dana Conlisk and Gabriela Goncalves Valente and Jean-François Wiart and Hélène Doat and Florian Hakim and Linda Boone and Mélodie Phanithavong and Camille Richeval and Giulia de Maio and Jean-François Fiancette and Jessica Tostain and Andrea Sepe and Bruno Megarbane and Jean-Michel Gaulier and Véronique Deroche-Gamonet},
journal = {Biomedicine and Pharmacotherapy},
year = {2026},
month = nov,
doi = {10.1016/j.biopha.2026.119801},
url = {https://hal.science/hal-05848712v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Individual differences in brain cocaine pharmacokinetics predict cocaine intake patterns in rats
AU - Dana Conlisk
AU - Gabriela Goncalves Valente
AU - Jean-François Wiart
AU - Hélène Doat
AU - Florian Hakim
AU - Linda Boone
AU - Mélodie Phanithavong
AU - Camille Richeval
AU - Giulia de Maio
AU - Jean-François Fiancette
AU - Jessica Tostain
AU - Andrea Sepe
AU - Bruno Megarbane
AU - Jean-Michel Gaulier
AU - Véronique Deroche-Gamonet
PY - 2026
DA - 2026/11/02
JO - Biomedicine and Pharmacotherapy
DO - 10.1016/j.biopha.2026.119801
UR - https://hal.science/hal-05848712v1
AB - 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.
SN - 0753-3322
SN - 1950-6007
ER -