Cocaine withdrawal alters the reward omission effect and enhances traits of negative urgency in rats across multiple days of testing

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Background The personality trait of negative urgency, characterized as behaving rashly when emotionally perturbed, is gaining attention as an indicator for susceptibility to problematic substance use. How this trait is influenced by exposure to drugs of abuse is still unclear. Using an animal model of binge cocaine consumption, we tested this relationship in a reward-omission task across multiple days. Methods Adult, male, Sprague-Dawley rats received seven daily (ip) injections of saline, cocaine (10-20 mg/kg), or cocaine (20-40 mg/kg). Cocaine doses increased linearly each day from the lower to the higher dose. A separate group received RTI-113 (3.0 mg/kg), a selective dopamine transporter inhibitor, for 7 days. Fifteen days after their final injection, rats were trained on a reward-omission task with an operant component to earn further rewards. Results Previous exposure to cocaine resulted in dose-dependent increases in negative urgency in separate behavioral variables across days of testing. The lower dose range increased negative urgency on the dimension of decreased reaction time to press a lever, while the higher dose range increased the rate of increase in lever presses made per trial. Rats receiving RTI-113 did not resemble either cocaine group and instead showed a decrease in lever pressing across days. Conclusions Our results indicate that previous binge cocaine consumption enhances behavioral markers of negative urgency in a dose-dependent, time-sensitive manner on discrete behavioral dimensions. The results with RTI-113 suggest the relationship between cocaine exposure and negative urgency is unlikely to be explained solely by inhibition of dopamine reuptake.

Effects of Cocaine Self-Administration and Its Extinction on the Rat Brain Cannabinoid CB1 and CB2 Receptors

“…In contrast to the above noted decreases in expression linked (mainly) to voluntary cocaine intake, the increases observed in tegmental CB1 receptor expression seem to be a pharmacological effect of cocaine delivery. It should also be noted that cocaine delivery in self-administering rats and yoked drug controls are linked with a conditioned stimulus, and the ventral tegmental area plays a significant role in learning and habit formation (Barker and Rebec 2016 ). In fact, Wang et al ( 2015 ) recently demonstrated the control of tegmental CB1 receptors over cocaine-induced synaptic plasticity and associative learning (Wang et al 2015 ).…”

Integrating Preclinical and Clinical Models of Negative Urgency

“…At present, studies investigating negative urgency in animals are sparse. One proposed method for generating negative urgency (utilized in both animal and human models) involves unexpected reward omission (56–58). In one study, humans or rats were trained to perform an operant task (button pressing or lever pressing, respectively) and were rewarded with either money or a food pellet, respectively (56).…”

“…In this study, higher polygenic 5HT scores (indicating lower 5HT function) were positively correlated with higher self-reported negative urgency and greater levels of alcohol consumption. At this time, there are no preclinical investigations evaluating the relationship between these transmitter systems, alcohol overconsumption, and negative urgency, although one study did report an increase in negative affect during cocaine withdrawal in rats in the reward omission task (58).…”