Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat

Abstract

Development of new treatments for drug addiction will depend on high-throughput screening in animal models. However, an addiction biomarker fit for rapid testing, and useful in both humans and animals, is not currently available. Economic models are promising candidates. They offer a structured quantitative approach to modeling behavior that is mathematically identical across species, and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity. However, economic demand has not yet been established as a biomarker of addiction-like behavior in animals, an essential final step in linking animal and human studies of addiction through economic models. We recently developed a mathematical approach for rapidly modeling economic demand in rats trained to self-administer cocaine. We show here that economic demand, as both a spontaneous trait and induced state, predicts addiction-like behavior, including relapse propensity, drug seeking in abstinence, and compulsive (punished) drug taking. These findings confirm economic demand as a biomarker of addiction-like behavior in rats. They also support the view that excessive motivation plays an important role in addiction while extending the idea that drug dependence represents a shift from initially recreational to compulsive drug use. Finally, we found that economic demand for cocaine predicted the efficacy of a promising pharmacotherapy (oxytocin) in attenuating cocaineseeking behaviors across individuals, demonstrating that economic measures may be used to rapidly identify the clinical utility of prospective addiction treatments.behavioral economics | reinstatement | extinction | long access | punished responding T here are currently no approved pharmacotherapies for the treatment of cocaine addiction, and timely development of future treatments will depend on animal models that predict the efficacy of treatment in human addicts. This requires a biomarker of addiction suitable for rapid testing in animals, and applicable in humans. However, animal models of neuropsychiatric diseases generally lack predictive validity (1, 2), and prevalent approaches that use drug self-administration in animals have not yet led to a successful clinical treatment for psychostimulant dependence (3, 4).Economic models provide more promising approaches for this needed cross-species addiction biomarker (5, 6). They offer a structured quantitative method to model behavior that is mathematically identical across species (7-9), and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity (10)(11)(12)(13)(14). Notably, economic demand has been shown to correlate with lifetime years of cocaine, heroin, marijuana, and benzodiazepine use (15); severity of alcohol dependence (10,11,14) and craving (16); as well as severity of nicotine dependence (12, 13) and craving (17). However, economic demand has not yet been established as a biomarker of addictionli...

Delay Discounting for Sucrose in Alcohol‐Preferring and Nonpreferring Rats Using a Sipper Tube Within‐Sessions Task

“…However, a previous report in rats indicated that there was not an association between demand for sucrose and DD of a sucrose reward (Koffarnus and Woods, 2013). Given that demand is often interpreted as a measure of motivation (Amlung et al, 2012; Bentzley et al, 2014; Zimmer et al, 2012), differences in sucrose motivation between rat lines are unlikely to account for the relatively higher DD in P rats reported here.…”

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine

“…10A; España et al, 2010; Oleson et al, 2011)). Once stable responding under the threshold schedule was achieved, data were fitted to an exponential demand curve to determine Q 0 , a measure of consumption at null cost, and P max , the behavioral economic index of price (Bentzley et al, 2014; Oleson et al, 2011). Under this schedule, Q 0 represents the animal’s preferred level of cocaine consumption while P max represents motivation to maintain preferred blood levels of cocaine.…”

“…In these studies we showed that susceptible subjects display increased motivation ( P max ) to obtain cocaine, with a corresponding decrease in consumption at null cost ( Q 0 ). This is a particularly interesting observation as motivation to obtain cocaine under the threshold schedule has recently been shown to positively correlate with several other features of an addiction-like phenotype including: (i) resistance to instrumental extinction, (ii) cue- and cocaine-induced reinstatement, and (iii) persistence of drug taking in the face of punishments (Bentzley et al, 2014). Furthermore, low initial levels of cocaine consumption were found to predict a heightened propensity to escalate cocaine taking (Bentzley et al, 2014).…”

“…This is a particularly interesting observation as motivation to obtain cocaine under the threshold schedule has recently been shown to positively correlate with several other features of an addiction-like phenotype including: (i) resistance to instrumental extinction, (ii) cue- and cocaine-induced reinstatement, and (iii) persistence of drug taking in the face of punishments (Bentzley et al, 2014). Furthermore, low initial levels of cocaine consumption were found to predict a heightened propensity to escalate cocaine taking (Bentzley et al, 2014). In consideration of the predictive nature of P max and Q 0 , it may be surmised that susceptible rats express a more expansive addiction-like phenotype.…”

Orexin/Hypocretin, Central Amygdala, and Escalation of Cocaine Intake

“…In this respect, the current study provides a strong starting point for understanding the role of orexin/hypocretin in pathological drug seeking but at the same time highlights a number of key questions that must be addressed by future studies. For example, the authors have elegantly implicated the orexin/hypocretin system as a key modulator of escalation of drug intake, but it remains to be demonstrated whether this mechanism is also involved in the regulation of other key addiction behaviors known to be enhanced by LgA such as compulsive (punished) responding and economic demand (8). Given the persistent nature of addiction, it is also important that future studies seek to determine whether the electrophysiological changes observed here immediately following cocaine self-administration persist into withdrawal and to what extent they contribute to relapse-like behavior.…”