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

Conlisk D(1), Goncalves Valente G(1), Wiart JF(2), Doat H(1), Hakim F(2), Boone
L(2), Phanithavong M(2), Richeval C(2), De Maio G(1), Fiancette JF(1), Tostain
J(1), Sepe A(1), Megarbane B(3), Gaulier JM(2), Deroche-Gamonet V(4).

Author information:
(1)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux F-33000,
France.
(2)CHU Lille, Unité Fonctionnelle de Toxicologie, Lille, France.
(3)Université Paris Cité, INSERM UMR-S 1144, Réanimation Médicale et
Toxicologique, Hôpital Lariboisière, Paris, France.
(4)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux F-33000,
France. Electronic address: .

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.

Copyright © 2026 The Authors. Published by Elsevier Masson SAS.. All rights
reserved.

DOI: 10.1016/j.biopha.2026.119801
PMID: 42526256 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.

Auteurs Bordeaux Neurocampus