Augmenter la vitesse d’infusion de la cocaïne par voie intraveineuse induit des changements neurochimiques, neurobiologiques et comportementaux chez le rat : implications pour la toxicomanie

Many individuals will experiment with cocaine during their lifetime; yet, few will transition from occasional drug use to addiction. Pharmacokinetic factors of the drug and the way it is consumed are important in this process. Drugs and routes of administration that produce the rapid rise of drug levels in the brain are believed to facilitate this transition. Similarly, intermittent access to the drug, which provokes fluctuations of cocaine concentrations in the brain rather than maintaining continuous high levels, may also be involved. The work presented in this thesis examines how speed of drug delivery and frequency of intake may induce addiction-like symptoms in a rat model of cocaine self-administration and promote neuroplasticity. In a first study, microdialysis was used to determine the effects of rate of cocaine infusion on cocaine and dopamine levels in the dorsal striatum of awake, freely-moving rats. Over the range of infusion rates used (5-90 seconds), cocaine and dopamine concentrations did not significantly vary. Instead, rapid cocaine infusions lead to the faster rate of onset of both molecules in the brain, implying that differences in cocaine-induced behaviour and neuroplasticity are not due to how much drug reaches the brain but on how fast the drug does so. Previous work from our laboratory showed that rapid cocaine infusions increase motivation for cocaine, a symptom of addiction. Therefore, we examined potential changes in the brain caused by rapid cocaine infusions in animals showing excessive motivation for the drug as assessed under a progressive ratio schedule of reinforcement. First, we investigated the effects of cocaine infusion rate on corticostriatal expression of brain-derived neurotrophic factor (BDNF) and TrkB mRNA in rats with a history of chronic and continuous exposure to cocaine under long access conditions (6 hours/session) and found that only rats self-administering rapid cocaine injections had altered BDNF and TrkB mRNA levels. Next, new evidence suggested that experienced cocaine users do not consume the drug continuously, but rather space out each intoxicating event. Therefore, using an intermittent access model of self-administration, where brain cocaine levels fluctuate within the session, we examined the effects of rate of infusion on c-fos mRNA expression, a marker of neuronal activity. A first group of rats had intermittent access to rapid cocaine infusions, a model we consider as addiction-relevant, while the second had access to slow and continuous cocaine, which promotes significant cocaine intake without promoting addiction-like behaviour. Animals in the addiction-relevant group presented greater motivation for cocaine and showed greater c-fos mRNA expression in various corticostriatal regions. Together, these results suggest that rapid and intermittent cocaine infusions facilitate the development of drug-induced neuroplasticity which may cause addiction-like behaviour, and particularly implicate the orbitofrontal cortex and the dorsal striatum. These two interconnected structures are both involved in addiction. Therefore, we temporarily and pharmacologically disconnected this circuit and found that it reduces motivation for cocaine. In conclusion, we show that pharmacokinetic factors are important when developing animal models of addiction, and that better understanding the mechanisms involved can potentially improve prevention and treatment therapies.

Keyphrases: Dopamine, Motivation, Addiction, Cocaine, Dopamine, Intermittent access, Long access, Microdialysis, Motivation, Rate of infusion, Progressive ratio