Behavioral Models of Cocaine Use Disorder

In chapter one, the lens of appetitive vs consumptive changes is used to discuss results from many rodent procedures in the self-administration literature. That is, the effects of a variety of drug experiences on subsequent changes in drug-seeking and/or drug-taking is explored. It is emphasized that building a better understanding of the underlying neurophysiological changes associated with either a change in drug-seeking, drug-taking or both provides a focus for targeted pharmacological interventions to treat various symptoms of substance use disorder. The literature reviewed in this chapter includes work from my own dissertation, and therefore places my work into the broader context of the self-administration literature.;In chapter two, a novel behaviorally dependent dosing (BDD) schedule was used to examine the relationship between doses of cocaine self-administered by rats and brain drug levels within a session. The BDD schedule used a hold-down response to activate a syringe pump. The length of time the lever was held down determined the duration that the syringe pump was activated. Animals self-administered larger doses immediately following each timeout period and the dose size was inversely correlated with the length of the timeout. These results show that the dose of cocaine that rats self-administer within a session is inversely related to the amount of drug on board.;In chapter three, we examined whether selection of dose size could be a factor in regulation of intake. We used a schedule of reinforcement, under which the dose can vary through a wide range and is determined by the behavior of the animal. Rats self-administered cocaine using a BDD schedule of reinforcement, under which the size of each dose was determined by the length of time the lever was held down. The concentration of cocaine was changed across sessions. Total pump-time self-administered decreased by 56 % following each doubling of the concentration, which led to an average 11 % increase in total intake. Similarly, estimated brain levels of cocaine increased by 12 % for each doubling of concentration. These adjustments were the result of manipulation of both the size and spacing of infusions. In agreement with previous studies, the regular pattern of intake appears to be the result of a titration mechanism in which animals maintain brain levels of cocaine above some threshold.;In chapter four, the acute effects of long-duration cocaine binges on appetitive responding was assessed. Human cocaine abusers typically develop a binge-abstinence pattern of use. The goal of the this study was to examine the time-course of motivation within a 24 hour cocaine binge. Additionally, the influences of circadian cycles, the transience of binge-induced decreases in breakpoint, and the effects of dose within a binge were examined. This study demonstrated that within a high-intake cocaine binge, motivation to self-administer decreases in a time-dependent fashion. These data add to a growing literature examining the role of psychostimulant binge administration.;Chapter five examined the consequences of a history of intermittent access to cocaine. We compared the effects of various cocaine self-administration procedures that produced very different patterns of drug intake and drug dynamics on Pmax, a behavioral economic measure of the motivation to self-administer drug. Cocaine levels could not be maintained with this procedure; instead the animals experienced 12 fast-rising spikes in cocaine levels each day. The IntA groups were compared with groups given 6-h FR1 long access and 2-h short access sessions and two other control groups. Here, we report that cocaine self-administration procedures resulting in repeatedly spiking drug levels produce more robust increases in Pmax than procedures resulting in maintained high levels of cocaine. These results suggest that rapid spiking of brain-cocaine levels is sufficient to increase the motivation to self-administer cocaine. (Abstract shortened by UMI.).