Cocaine Is Low on the Value Ladder of Rats: Possible Evidence for Resilience to Addiction

Abstract

BackgroundAssessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats – by far the most frequently used animal model in this field – suggest that the value of cocaine is lower than previously thought.Methodology/Principal FindingsHere we report a series of choice experiments that better define the relative position of cocaine on the value ladder of rats (i.e., preference rank-ordering of different rewards). Rats were allowed to choose either taking cocaine or drinking water sweetened with saccharin – a nondrug alternative that is not biologically essential. By systematically varying the cost and concentration of sweet water, we found that cocaine is low on the value ladder of the large majority of rats, near the lowest concentrations of sweet water. In addition, a retrospective analysis of all experiments over the past 5 years revealed that no matter how heavy was past cocaine use most rats readily give up cocaine use in favor of the nondrug alternative. Only a minority, fewer than 15% at the heaviest level of past cocaine use, continued to take cocaine, even when hungry and offered a natural sugar that could relieve their need of calories.Conclusions/SignificanceThis pattern of results (cocaine abstinence in most rats; cocaine preference in few rats) maps well onto the epidemiology of human cocaine addiction and suggests that only a minority of rats would be vulnerable to cocaine addiction while the large majority would be resilient despite extensive drug use. Resilience to drug addiction has long been suspected in humans but could not be firmly established, mostly because it is difficult to control retrospectively for differences in drug self-exposure and/or availability in human drug users. This conclusion has important implications for preclinical research on the neurobiology of cocaine addiction and for future medication development.

Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

“…Indeed, we recently found that most rats trained to self-administer both food and methamphetamine prefer the food pellets (Caprioli and Shaham, unpublished data). These data confirm previous results of Ahmed and Lenoir that the majority of rats trained for cocaine self-administration strongly prefer an alternative non-drug food reward (saccharin solution) (Ahmed et al, 2013;Cantin et al, 2010;Lenoir et al, 2007). A question for future research is whether both resistance to punishment and preference for food over methamphetamine would be reversed in rats classified as 'addicts' following months of drug self-administration in the DSM-based addiction model developed in Bordeaux (Deroche-Gamonet and Piazza, 2014;Piazza and DerocheGamonet, 2013).…”

Choosing Under the Influence: A Drug-Specific Mechanism by Which the Setting Controls Drug Choices in Rats

“…Importantly, a 10-min intertrial interval was used here, as well as in all previous experiments from this laboratory, because it takes ∼ 10 min for the locomotor effects of the testing dose of cocaine (0.25 mg) or heroin (0.01 mg) to dissipate (Cantin et al, 2010;Lenoir et al, , 2013. As a result, this procedure defines a setting where choosing under the drug influence is not possible or only minimal, even if rats happen to choose cocaine on most trials.…”

“…There is growing awareness that such lack of options may limit the validity of this research for understanding drug addiction as a drug use disorder (Ahmed, 2005(Ahmed, , 2010Ahmed et al, 2013;Alexander and Hadaway, 1982;Cantin et al, 2010;Caprioli et al, 2015b;Carroll et al, 1989;Kerstetter et al, 2012;Le Sage, 2009;Lenoir et al, , 2013Liu and Grigson, 2005;Perry et al, 2013;Thomsen et al, 2013;Tunstall and Kearns, 2013;Zernig et al, 2013). Indeed, when there is no valuable alternative to the drug, drug self-administration may merely reflect a normal reaction to the lack of choice as opposed to reflecting a disordered behavior caused by an underlying dysfunction (Ahmed, 2010;Ahmed et al, 2013;Hyman and Malenka, 2001).…”

“…In most of these studies, virtually all rats rapidly and almost completely stopped drug use in favor of the competing option (Cantin et al, 2010;Carroll and Lac, 1993;Carroll et al, 1989;Kerstetter et al, 2012;Le Sage, 2009;Lenoir et al, , 2013Madsen and Ahmed, 2015;Perry et al, 2013;Tunstall and Kearns, 2013;Tunstall et al, 2014). Suppression of cocaine use in favor of sweet reward developed even after extended access to cocaine self-administration and could not be surmounted by maximally increasing the dose of cocaine (eg, up to 1.5 mg per injection) (Cantin et al, 2010;. Remarkably, a complete and long-term suppression of methamphetamine seeking by food choice was also demonstrated in rats after different histories of extended access to methamphetamine self-administration that are known to induce addiction-like behavior (Caprioli et al, 2015a, b).…”

Varieties of Voice-Hearing: Psychics and the Psychosis Continuum

“…11 However, this has yet to be converted into new therapeutic approaches. 13 Here we consider what may protect nonclinical voice hearers, inspired by similar studies in addiction, 14 oncology, 15 and infectious diseases 16,17 : there are individuals who are resilient despite similar exposure to risk factors as individuals who become ill.…”