The Importance of the Temporal Pattern of Drug Use in Addiction

Abstract

Drug addiction affects tens of millions of people worldwide and yet there is no biological marker for diagnosis and available treatment options remain largely ineffective. Interestingly, of the individuals that recreationally use drugs of abuse only a subset eventually develop the problematic patterns of use that define addiction. The question to be addressed in this dissertation is how brain and psychological function change in susceptible individuals during the transition from recreational drug use to addiction. Preclinical models of addiction offer the opportunity to study specific aspects of addiction through manipulations that would not be possible in humans and are thus invaluable in the study of addiction. Currently, the most widely used preclinical self-administration models of addiction stress the amount of drug an individual consumes, and suggest that addiction can only occur following the consumption of large quantities of drug. While the amount of drug consumed is important in the development of addiction it is only one factor that contributes. The pharmacokinetics of drug use are also important in the development of addiction. This is especially important when considering that human drug use tends to be intermittent both between and within bouts of use during the transition from casual drug use to addiction. However, until recently intermittent patterns of drug intake have largely not been studied in preclinical self-administration models. In the studies presented here we developed a novel procedure for modeling the development of cocaine addiction by combining a recently introduced intermittent access (IntA) self-administration procedure with an established prolonged access procedure. We found that this procedure produced remarkably robust addiction-like behavior when measured on a variety of tests. In chapter 2 we used this procedure to investigate individual differences in the susceptibility to develop addiction-like behavior in rats that are especially prone to attribute incentive-salience to reward-paired cues (sign-trackers; STs) versus rats less prone to do so (goal-trackers; GTs). We found that STs were more motivated to self-administer cocaine prior to IntA experience, but following prolonged IntA, all individuals developed addiction-like behavior such that STs and GTs no longer differed. In chapter 3, we used a similar experimental design to study sex differences in the development of addiction-like behavior. We found that females were far more motivated to work for cocaine than males following prolonged IntA self-administration. The magnitude of this difference was larger than what is typically seen in studies examining both sexes, suggesting that females may be particularly susceptible to the effects of intermittent cocaine exposure. Finally, in chapter 4 we sought to elucidate the neural mechanisms that promote the development of addiction-like behavior following IntA, and how these processes may differ as a function of the temporal pattern of cocaine experience. We found that the temporal pattern of cocaine intake had a large impact on subsequent motivation for cocaine and the increased motivation observed following IntA was strongly correlated with sensitized DA release in the nucleus accumbens core in response to cocaine. Taken collectively these studies show that consuming large amounts of cocaine is not necessary for the development of addiction-like behavior, and that intermittent cocaine experience is very effective at producing addiction-like behavior via a sensitized mesolimbic dopamine response to cocaine.