Manipuler la pharmacocinétique de la cocaïne chez le rat pour comprendre et traiter un phénotype toxicomane

Taking a drug does not mean that you are a drug addict. Drug addiction is a neuropsychiatric disorder and only few people who take cocaine will lose control of their consumption. Part of the reason comes from the pattern of drug use, which can change the pharmacokinetics of cocaine. How much, how fast and how often the drug is administered are pharmacokinetic variables of cocaine that can be decisive in the drug addiction process. During my Ph.D. I was interested in modeling these pharmacokinetic variables in rats and determining their impact on the development of an excessive motivation for cocaine – a drug addiction symptom. Typically, in preclinical research on drug addiction, rats can self-administer cocaine continuously during extended sessions (LgA-rats). Within such LgA sessions, high brain cocaine levels are maintained. These elevated cocaine levels promote both the intake of large amounts of cocaine that increase over time and the development of clinically relevant drug addiction symptoms. Thus, taking large amounts of cocaine has long been considered as the principal factor in the transition toward a drug addiction phenotype. In rats that self-administer cocaine intermittently (IntA-rats), brain cocaine levels fluctuate within sessions. We limited the maximum number of cocaine injections available during IntA sessions in order to promote the intake of low levels of cocaine that stay stable over time. In two groups of IntA-rats that self-administer similar amounts of cocaine, those exposed to rapid injections of cocaine developed a neurobehavioral plasticity thought to be relevant to drug addiction (excessive motivation for cocaine and glutamate homeostasis dysregulation) compared to those exposed to slower injections. Thus, independently of the amount of cocaine taken, the speed of cocaine delivery can drastically increase the development of a drug-addiction phenotype. We next showed that motivation for cocaine in IntA-rats that self-administer rapid injections of the drug was the same whether cocaine intake was limited or not. This suggests that rapid spikes in brain cocaine levels (presumably leading to spikes in dopamine levels) pose a greater risk than a continuous and excessive exposition to cocaine for developing drug-addiction symptoms. Indeed, IntA-rats, whose self-administration is strictly limited to very low levels of cocaine, consequently develop higher motivation for cocaine than LgA-rats with free and continuous access to the drug. Finally, co-release of amphetamine during intermittent cocaine self-administration reduces the motivation for cocaine. This efficacy of amphetamine can be the result of its ability in widening/flattening brain dopamine spikes. A better understanding on the reasons underlying whether or not a drug addiction phenotype develops when we vary the pharmacokinetics of cocaine is a key determinant in developing treatments for drug addiction.

Keyphrases: Accès continu, Accès intermittent, Amphetamine, Amphétamine, Cocaine, Cocaïne, Dopamine, Drug addiction, Glutamate, Intermittent-access, Long-access, Pharmacokinetics, Rats, Self-administration