Examination of Addiction Relevant Psychomotor Activation and Incentive Motivation Following Intermittent Access to Cocaine Self-Administration

Abstract

Many people have tried an addictive drug at some point in their lifetime, but only a small percentage of these individuals develop compulsive patterns of drug use that define a substance abuse disorder. For ethical reasons, amongst many others, it is difficult to study the transition from casual to compulsive use in humans. As a result, a number of preclinical self-administration models have been developed to investigate the neurobiological and psychological mechanisms underlying addiction susceptibility. For over a decade, long access (LgA; 6-h sessions of continuous drug availability) self-administration was the most widely used preclinical model of addiction, the results of which suggest that high and escalated drug intake is necessary for the development of addiction-like behavior. Human cocaine users, however, rarely engage in sustained high-level use and instead opt for a more sporadic pattern of administration. Recently, intermittent access (IntA; 5-min Drug-Available periods separated by 25-min No Drug-Available periods) was developed to better model human cocaine use patterns and the results from this model show more robust addiction-like behavior despite less drug consumption. Intermittent patterns of use have also been shown to result in sensitization to the psychomotor activating effects of drugs. This behavioral plasticity is thought to reflect, in part, changes in dopamine (DA) neurotransmission, and therefore, may provide insights into the development of addiction. Currently, the growing literature on IntA suggests that IntA better models the transition to addiction but very little is known about the ability of IntA to produce psychomotor sensitization. Early studies of intermittent, experimenter-administered cocaine revealed several characteristics of psychomotor sensitization, inclusive of, but not limited to: (1) greater expression after extended vs acute withdrawal, (2) greater expression in females compared to males, and (3) cross-sensitization to other drugs of abuse. In Chapter II, we found that self-administered cocaine under IntA conditions produced psychomotor sensitization with similar characteristics. Specifically, our first experiment revealed a left shift in the dose-effect function (indicative of psychomotor sensitization) in animals with IntA but not LgA experience when tested one day after discontinuation of self-administration (withdrawal day 1). Following extended withdrawal (30 days) from IntA, an even greater drug effect was observed, as indicated by focused stereotyped head movements. Robust psychomotor sensitization was also observed following extended withdrawal from LgA, with neither stereotypy ratings nor frequencies differing from IntA animals. In our second experiment, we utilized IntA-Limited to ensure similar consumption in females and males and assessed psychomotor sensitization within and between subjects. We found that females with IntA-Limited experience increased locomotor activity to a greater extent across sessions than males with IntA-Limited experience. Even though both females and males expressed psychomotor sensitization in the self-administration context, only females with IntA-Limited experience expressed psychomotor sensitization outside of the self-administration context compared to sex-matched, drug-exposed controls. In a separate experiment, we also found a greater locomotor response to d-Amphetamine challenge doses in animals with IntA cocaine self-administration experience compared to acquisition-only controls. Lastly, in Chapter III, we found comparable incentive sensitization, as assessed by a behavioral economic approach, in females and males that was positively correlated with the extent of psychomotor sensitization expressed following IntA-Limited. These results add to the literature showing that the IntA model is especially effective at producing the neurobehavioral sensitization thought to underlie the transition to addiction, and thus support an incentive-sensitization view of addiction.