Dopaminergic mechanisms of cocaine use

Abstract

Cocaine addiction is an enormous medical problem for which there is currently no effective pharmacotherapy. In order to develop treatments for this disorder, it is essential to understand the neurobiological underpinnings of cocaine addiction. One of the behavioral characteristics of addiction is an excessive motivation for drugs. This thesis focuses on this motivational aspect and aims to expand our understanding of how drugs, such as cocaine, usurp neurobiological systems that under normal conditions regulate the motivation for rewards. To this end, the role of dopaminergic and glutamatergic neurotransmission in motivational behaviors associated with addiction was studied in rats during the early stages of cocaine experience. In this thesis, three different approaches were taken to enhance our understanding of the neural substrates of the rewarding and motivational properties of cocaine. These experiments are presented in three chapters. In chapter 2 we investigated the role of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of cocaine and morphine. We systemically administered the mGlu5 receptor antagonist MTEP and the dopamine receptor antagonist alpha-flupenthixol during the development of cocaine and morphine conditioned place preference and psychomotor sensitization. We found that mGlu5 receptors play a drug-specific role in drug reward and sensitization. In addition, dopamine receptor stimulation is critical for mediating cocaine and morphine reward but not sensitization. Self-administration models have greater face validity than place preference and psychomotor sensitization paradigms. Since we were particularly interested in the neurobiology of the motivational aspects of drug use, we evaluated two self-administration paradigms to measure the motivation for sucrose and cocaine. The two paradigms under investigation in the studies described in chapter 3 were seeking-taking chain schedules of reinforcement, with either a random-interval or a progressive ratio requirement on the seeking link, and a fixed ratio-1 requirement on the taking link. We compared the sensitivity of these schedules using different manipulations to affect the motivation to respond for cocaine and sucrose. To this aim, we varied the reward size, omitted the reward, and systemically administered the dopamine receptor antagonist alpha-flupenthixol. We found that both schedules tested can be used to measure motivation properties of sucrose and cocaine. It has been hypothesized that the descent from casual drug use into addiction is the result of drug-induced neural changes that progress from ventral to dorsal striatum. In Chapter 4 we examined the involvement of striatal dopamine in the motivation for cocaine in animals with limited or no cocaine self-administration experience. To accomplish this, we infused the dopamine receptor antagonist alpha-flupenthixol into different regions of the striatum, in animals that responded for cocaine under a fixed-ratio 1 or a seeking-taking(progressive ratio) schedule of reinforcement. We found that NAcc shell dopamine mediates the motivation to take cocaine and that DLS dopamine, in contrast to the hypothesis, mediates cocaine reward after limited drug experience already. Together, the results of the experiments described in this thesis add to our understanding of the role of neural mechanisms involved in the initial stages of addiction.