Human Cocaine-Seeking Behavior and its Control by Drug-Associated Stimuli in the Laboratory

Abstract

Second-order schedules of drug self-administration were developed to incorporate the effects of drug-related environmental stimuli into an animal model of drug abuse, making it more similar to human situations. Ironically, little is known about how human subjects behave under these schedules. In this study, human volunteers with a history of cocaine use worked on a second-order schedule in which every 100th lever response produced an auditory-visual brief stimulus (2 s). The first stimulus produced after 1 h was extended to 10 s and paired with an intravenous injection of cocaine (25 mg). Up to three injections were allowed per session. In different phases of the experiment, presentation of the brief stimulus was discontinued and/or saline solution (placebo) was injected instead of cocaine. Injections of cocaine were found to maintain responding even when the brief stimulus was not presented. Placebo injections alone did not maintain responding. In contrast, the brief stimulus maintained high levels of responding under placebo conditions, even though selfreports indicated that subjects could clearly discriminate that they were not receiving cocaine. These results demonstrate that drugrelated environmental stimuli can maintain persistent drug seeking during periods of drug unavailability. As this procedure directly measures the effects of stimuli on drug seeking, it may provide a valuable complement to indirect measures, such as self-reports of craving, that are often used with human subjects. The similarity of the response patterns in humans and animals also supports the use of second-order schedules in animals as a valid model of human drug seeking.

Involvement of the Dorsal Striatum in Cue-Controlled Cocaine Seeking

“…In rodents and primates, second-order schedules of reinforcement provide a well established method of investigating the neurobiology of drug seeking that is under the control of drug-associated CSs (Goldberg et al, 1975;Everitt and Robbins, 2000;Schindler et al, 2002). Indeed, cocaine seeking under a second-order schedule of reinforcement in humans shares many similarities to that observed in rats and monkeys (Panlilio et al, 2005).…”

“…Drug-paired conditioned stimuli (CSs) can, as conditioned reinforcers, maintain drug seeking and precipitate drug craving and relapse (Stewart et al, 1984;Ehrman et al, 1992;Carter and Tiffany, 1999;Everitt and Robbins, 2000;Schindler et al, 2002;Panlilio et al, 2005). In rodents and primates, second-order schedules of reinforcement provide a well established method of investigating the neurobiology of drug seeking that is under the control of drug-associated CSs (Goldberg et al, 1975;Everitt and Robbins, 2000;Schindler et al, 2002).…”

Randomized trial of prize-based reinforcement density for simultaneous abstinence from cocaine and heroin.

“…In preclinical studies, second-order schedules of reinforcement have been shown to support robust and persistent operant responding for both natural and drug reinforcers (Alderson, Robbins, & Everitt, 2000;Goldberg, Kelleher, & Goldberg, 1981;Goldberg & Tang, 1977;Katz, 1979Katz, , 1980Mello et al, 1995). In addition, laboratory studies suggest that humans will learn to respond to a variety of reinforcers under second-order schedules (Lamb et al, 1991;Mello, Mendelson, Palmieri, Lex, & Teoh, 1990;Panlilio et al, 2005).In applying an operant schedule that has reliably been demonstrated to produce robust and prolonged responding with relatively low-cost prizes, the procedure used here may have important clinical benefits, reinforcing abstinence in a cost-effective manner. Our patients in the high-density contingent group received prizes worth on average only $286 during the 12-week intervention, less than the cost of commonly studied voucher-based CM procedures (Downey, Helmus, & Schuster, 2000;Higgins, Badger, & Budney, 2000;Piotrowski et al, 1999;Robles et al, 2000;Silverman et al, 1996).…”

The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking

“…The invigorating impact of drug-associated conditioned stimuli (CSs) on seeking behavior has been operationalized in models of CS-induced relapse (Ciccocioppo et al, 2002;Gipson et al, 2013;Lee et al, 2006;Marchant et al, 2013) as well as cue-controlled cocaineor heroin-seeking behavior (Arroyo et al, 1998;Economidou et al, 2011;Giuliano et al, 2013) and CS-dependent seeking of high incentive foods that is associated with obesity and binge eating (Giuliano et al, 2012). Although outbred rat strains will respond instrumentally for alcohol (Augier et al, 2014), and alcohol-associated CSs can elicit approach (Tomie and Sharma, 2014) and serve as conditioned reinforcers (Smith et al, 1977;Panlilio et al, 2004;Milton et al, 2012;Rodd et al, 2004), attempts to establish vigorous CS-dependent alcohol seeking that mediates delays to the opportunity to drink have proven difficult, probably because alcohol is an apparently weak reinforcer for rats with little or no propensity to drink.…”