Cocaine-Seeking Behavior

Chapter 41

Cocaine-Seeking Behavior: Comparisons to Food-Seeking Behavior and Potential Treatments B.J. Tunstall1 and D.N. Kearns2 1

National Institute on Drug Abuse, Baltimore, MD, United States, 2American University, Washington, DC, United States

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Fixed ratio-1 (FR-1) schedules permit simple measurement of reinforcer consumption. Animals have higher progressive ratio (PR) breakpoints and more inelastic demand for food compared to cocaine, and the majority of animals prefer food to cocaine. Cocaine- but not food-motivated behaviors can become more habitual and driven by negative reinforcement as a result of extended access. Cocaine cues have the ability to become stronger than food cues, even when food is the preferred alternative. Several avenues for developing cocaine-cue-targeted treatments exist and may offer a means for disrupting persistent cocaine-seeking behavior.

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The fixed-ratio 1 schedule measures reinforcer consumption, likely limited by satiety or side effects. Progressive-ratio schedules measure motivation for reinforcer, but are contaminated by reinforcer strength. Demand curve analyses measure resistance of reinforcer consumption to changes in price, to determine the elasticity of reinforcer demand. Choice procedures offer concurrent reinforcement alternatives in order to measure reinforcement strength relative to an alternative. Reinstatement tests measure reappearance of reinforcer seeking in response to motivating events.

The Neuroscience of Cocaine. DOI: http://dx.doi.org/10.1016/B978-0-12-803750-8.00041-5 © 2017 Elsevier Inc. All rights reserved.

conditioned reinforcer conditioned stimulus fixed ratio progressive ratio unconditioned stimulus

41.1 INTRODUCTION The motivation to earn and consume a reinforcer is not easily assessed in situations where the organism has constant and unimpeded access to reinforcement. This scenario is approximated by the fixed ratio (FR) 1 schedule of reinforcement, where only a single operant response (e.g., lever press or nosepoke) is required to cause reinforcement delivery. In such situations, the consumption of the reinforcer will be predominantly dictated by reinforcer strength, satiation, and side effects of the reinforcer. Thus, situations in which constraints are placed upon consumption are useful, as they allow an assessment of the organism’s willingness to “seek” or “work” for reinforcement. Disentangling reinforcement from the motivation to seek it is difficult, as these factors work in concert. As discussed by Wise (1987), instrumental responses required to access reinforcement can be separated from the consummatory response, one which terminates a reinforced sequence of behaviors (e.g., eating food, drinking water). In studying intravenous cocaine reinforcement on an FR-1 schedule, this separation is not present. This is because a single lever press begins the drug infusion, with no subsequent ingestion response required. While it is possible to

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establish a consummatory response in a chain of drugmaintained behavior, it is difficult to imagine this response having the ethological relevance of true ingestive responses. Intravenous drugs of abuse such as cocaine are unusual as reinforcers because they do not have stereotyped, highly conserved, ingestion responses (e.g., licking, chewing; Wise, 1987). This is highlighted well in work comparing autoshaping (or “sign-tracking”) to a conditioned stimulus (CS) predictive of either food or cocaine unconditioned stimuli (US; Kearns & Weiss, 2004; Uslaner, Acerbo, Jones, & Robinson, 2006). With a food or liquid US, a predictive CS such as a lever will generally elicit a conditioned response which takes the form of the US ingestive response, but is directed toward the CS. As shown in the left panel of Fig. 41.1, even when rats are trained to make a consummatory response for cocaine (a lever press), they do not develop significant sign-tracking behavior toward a highly compatible CS (a second lever). However, once the cocaine US is replaced with a food US, rats quickly express vigorous contact behavior with the lever CS (biting, gnawing; Fig. 41.1, right panel). The ingestive response for palatable food is intrinsically linked to reinforcement (via taste and smell), regardless of postingestive consequences. Artificial sweeteners (e.g., saccharin) are readily ingested by rats and humans despite lacking caloric content and saccharin preference can even be demonstrated in the unusual case of newborn animals without prior feeding experience, indicating that conditioned reinforcement (sweet tastes are usually CS lever Consummatory lever

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FIGURE 41.1 Rats sign-track to a food US but not a cocaine US. Mean percentages ( 6 SEM) of trials (two-session blocks) with at least one contact, for rats trained on a procedure where a lever CS predicted availability of reinforcement via a second lever that required a contact consummatory response. Left: trials in which intravenous cocaine was the reinforcer. Right: trials in which food was the reinforcer. Reproduced from Kearns, D. N., & Weiss, S. J. (2004). Sign-tracking (autoshaping) in rats: A comparison of cocaine and food as unconditioned stimuli. Animal Learning & Behavior, 32(4), 463 476 with permission from Springer.

predictive of calories) cannot alone account for saccharin’s reinforcing properties (Foster, 1968). In contrast, ingestion responses for cocaine (snorting or smoking) appear to be a means to a pharmacological end (although ingestion responses may acquire conditioned reinforcing properties after repeated cue drug pairing). Drugs of abuse appear to have reinforcing actions by “tapping in” directly to highly conserved brain circuitry that originally developed in concert with sensory systems to organize and execute essential survival behavior, such as seeking and consuming calories (Mu¨ller & Schumann, 2011; in particular 4.2.7; Volkow, Wang, Tomasi, & Baler, 2013). An array of behavioral techniques has made it increasingly clear that cocaine- and food-seeking behaviors have important differences (Kearns, Gomez-Serrano, & Tunstall, 2011). An understanding of these differences may offer insights for the development of treatments for maladaptive cocaine seeking.

41.2 MEASURING DRUGAND FOOD-SEEKING BEHAVIOR 41.2.1 Simple Schedules Reinforcement is the process by which responses are strengthened by their outcomes. However, reinforcer seeking refers to behaviors oriented toward the attainment of reinforcement. In theory, reinforcer seeking leads to reinforcement, which is how reinforcer-seeking behavior is maintained. Situations in which the amount of reinforcer seeking becomes disproportionate to the amount of reinforcement received are of particular interest for understanding addictive behavior. Different schedules of reinforcement can produce differences in the ratio of seeking to reinforcement, which allows analysis of the role of cocaine seeking in addiction-like behavior. In the FR-1 schedule of reinforcement, every response is reinforced. This is the most commonly used schedule in preclinical drug abuse research, as the animal quickly learns to selfadminister cocaine infusions. Despite the simplicity and robustness of this measure, the determinants of reinforcer consumption in this situation may have little to do with reinforcer strength or the animal’s motivation for the reinforcer. For example, if one strongly desires their regular cup of coffee in the morning, we might fail to detect this strong desire by simply measuring the individual’s drinking when offered unlimited coffee. While reinforcement drives the coffee consumption, satiation or unpleasant effects resulting from excessive reinforcer consumption will dictate the limit of that consumption (perhaps a second cup of coffee adds little to the experience, and three cups makes the individual feel jittery). In contrast, on an FR-100 schedule of reinforcement, the ratio of work to reinforcement is quite high (100

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responses to one reinforcer), and with the animal held below its ideal level of consumption, it quickly becomes clear how motivated the animal is to receive a drug infusion. For example, a better test of the value of morning coffee to the aforementioned individual may be to make it increasingly difficult to obtain coffee. We may find in this scenario, the individual is willing to wait in rather long lines or pay high cafe´ prices to ensure they get their regular morning cup of coffee.

41.2.2 Seeking Taking Chains Chained schedules have been used to separate instrumental “seeking” and “taking” components of drug-motivated behavior. The rat must complete a response requirement (usually a random interval schedule) on the seeking lever in order to gain access to a second lever—the taking lever. A single press on the taking lever then results in delivery of a drug infusion, and a new seeking taking cycle is initiated. Thus, drug-seeking and drug-taking responses in this schedule are physically distinct. The seeking taking chain procedure has uncovered a number of notable differences between seeking and taking behavior. One of the most important of these is the effect of cocaine dose on behavior. Olmstead, Parkinson, Miles, Everitt, and Dickinson (2000) found that as dose increased, the number of cocaine-taking responses decreased. Interestingly, however, cocaine-seeking response rate increased with increases in dose. When sucrose was the reinforcer instead of cocaine, the rate of both seeking and taking responses increased with increased sucrose concentration. This suggests that larger doses of cocaine are more motivating than smaller doses, although this effect can only be observed when seeking behavior is measured separately from taking behavior, which is presumably limited by satiation or aversive effects of cocaine. Additionally, Olmstead, Lafond, Everitt, and Dickinson (2001) found that with limited access to cocaine, extinction of the cocaine-taking response led to a decrease in the rate of cocaine seeking. However, with a prolonged history of cocaine self-administration, extinction of the taking response appears to have little effect on cocaine seeking (Zapata, Minney, & Shippenberg, 2010). Furthermore, following extended access to cocaine, rats develop punishment-resistant cocaine seeking (Pelloux, Everitt, & Dickinson, 2007). These results suggest that with increasing cocaine exposure, cocaine seeking transitions from goal-directed to habitual, compulsive-like behavior.

41.2.3 Progressive Ratio Schedules There are many ways to impose an obstacle to consumption (i.e., raising the response cost). In behavioral

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pharmacology, there is a long history of using progressive ratio (PR) schedules to assess motivation for reinforcement (for review, see Richardson & Roberts, 1996). On a PR schedule, the number of responses required for the next reinforcement increases with each reinforcer earned. Here, the maximum number of responses emitted by the subject and the ratio requirement at which the animal finally “gives up” (the “breakpoint”; Hodos, 1961), can be determined. Early findings from PR work comparing cocaine and food reinforcement suggested that, in contrast to the addictive potential of the reinforcers, food is a stronger motivator of behavior than cocaine (e.g., Spear & Katz, 1991). A difficulty of using PR schedules to compare cocaine and food is that they are freely consumed at different rates. For example, a rat may self-administer 1-mg/kg/inf cocaine at the rate of 10 infusions per hour, but eat over 200 food pellets in the same period of time. In this case, one infusion would represent 10% of unconstrained cocaine intake, whereas one pellet would represent only 0.5% of unconstrained food intake. However, if compared directly on a PR schedule, the rat will have to emit the same number of responses to earn these very different fractions of unconstrained intake.

41.2.4 Demand Analyses Behavioral economic concepts can be used to assess the strength of drug- and food-seeking behavior. This involves the analysis of demand curves (Hursh & Silberberg, 2008). Briefly, an organism’s consumption of a reinforcer is measured at various prices. The price of a reinforcer can be stated as cost (e.g., required lever presses) divided by the amount of reinforcement (e.g., cocaine dose, food pellets). Price can be manipulated in several ways. Most commonly, it is done by increasing the response requirement (i.e., price) for a fixed amount of reinforcement within a fixed time period. Demand curves are generated by plotting consumption as a function of price. Several behavioral economic variables can be derived from demand curves. Perhaps the most important for the purpose of measuring the vigor of reinforcer-seeking behavior is demand elasticity. This describes the rate of change in consumption as price increases. Demand is considered elastic when decreases in consumption are proportionately larger than increases in price. Demand is inelastic when price increases have relatively small effects on consumption. In line with PR data, but again in apparent contradiction to the addictive potential of the reinforcers, studies that directly compared cocaine and food have demonstrated that demand for cocaine is more elastic than the demand for food (Christensen, Silberberg, Hursh, Huntsberry, & Riley, 2008a).

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41.2.5 Choice Procedures A different approach to assessing constrained cocaine self-administration is offering cocaine in a situation where the animal must make a mutually exclusive choice between cocaine and a nondrug alternative. In a commonly used procedure (for reviews, see Ahmed, 2010; Vanderschuren & Ahmed, 2013), each choice is a discrete trial wherein the animal may pick one of the alternatives. Here, the animal must forego the food pellet to selfadminister cocaine. Work in rodents suggests that the primary reinforcing strength of cocaine is low in most animals, with the majority of rats foregoing cocaine to earn food or sweet solutions (see Fig. 41.2). However, one compelling observation from these studies is that a subset of animals demonstrate a persistent preference for cocaine over food (Cantin et al., 2010; Lenoir, Serre, Cantin, & Ahmed, 2007; Perry, Westenbroek, & Becker, 2013; Tunstall & Kearns, 2013, 2014, 2015). Care is needed in interpreting the results of choice studies. The preference between alternatives is a dynamic process impacted by several factors such as price, satiation, delay to alternatives, the interaction of earned reinforcers, and the availability and substitutability of reinforcers within and outside of the choice context (Banks & Negus, 2012; Banks et al., 2015). Recent studies have demonstrated that mutually exclusive choice between food and cocaine with short intertrial intervals (ITIs) results in a higher preference for cocaine than when longer intertrial intervals are used (Kerstetter et al., 2012; Vandaele, Cantin, Serre, Vouillac-Mendoza, & Ahmed, 2016). This has been attributed to the anorectic 100 90 % Cocaine choice

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FIGURE 41.2 Rats prefer food to cocaine. Mean percentage ( 6 SEM) of free-choice trials (1 mg/kg/inf cocaine and one 45-mg grain pellet concurrently available; 14 trials per session) on which cocaine was chosen, across five sessions. *p , 0.05, different from 50% (i.e., no preference). Reproduced from Tunstall, B. J., & Kearns, D. N. (2013). Reinstatement in a cocaine versus food choice situation: Reversal of preference between drug and non-drug rewards. Addiction Biology. http://dx.doi.org/10.1111/adb.12054 [e-pub ahead of print] with permission from Wiley.

effects of cocaine, which diminish the reinforcing properties of food. Thus, choice of cocaine likely promotes further cocaine choice through diminution of the nondrug alternative’s value (Vandaele et al., 2016). These findings may explain the results of early studies where rats with continuous access to cocaine would self-administer it in long bouts, foregoing available alternative activities maintained by nondrug reinforcement (e.g., eating, drinking, and grooming), in some cases until death (Bozarth & Wise, 1985). By imposing a sufficiently long ITI between opportunities to choose between cocaine and food, the appetite-suppressant effects of cocaine dissipate before the next choice and the majority of animals demonstrate preference for food (Kerstetter et al., 2012; Tunstall & Kearns, 2013, 2015; Vandaele et al., 2016).

41.2.6 Extended-Access Procedures An escalation of consumption and increase in the motivation to seek cocaine (and most other drugs of abuse) emerges following extended access to the drug (for review, see Edwards & Koob, 2013). With an escalation of drug self-administration, there is a well-established emergence of an anhedonic state in the absence of the drug, including an upward shift in reward threshold and the dysregulation of stress systems (Ahmed, Kenny, Koob, & Markou, 2002; Koob, 2013). Initially, the positive reinforcing properties of drugs are what maintain drug taking, whereas in the transition to dependence, drugs also serve to alleviate the unpleasant state which emerges in their absence (through negative reinforcement; Koob, 2013; George, Koob, & Vendruscolo Leandro, 2014). Interestingly, extended access to cocaine decreased the elasticity of demand for it, whereas a similar effect was not observed for food (Christensen, Silberberg, Hursh, Roma, & Riley, 2008b). Furthermore, preference for cocaine (over food) increases along with PR breakpoint for cocaine following a long history of cocaine selfadministration (Perry, Westenbroek, Jagannathan, & Becker, 2015; though see Lenoir, Cantin, Vanhille, Serre, & Ahmed, 2013). The emergence of a negative emotional state following extended access to cocaine but not food, could explain increased demand for and choice of cocaine. With a long enough history of drug abuse, the motivation for cocaine could become so strong that it makes cessation difficult, and the impact of available alternatives minimal.

41.2.7 Conditioned Reinforcement and Cocaine Seeking Through repeated pairings with cocaine, cues predictive of cocaine-taking become reinforcers in their own right (i.e., conditioned reinforcers). These cues are able to

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41.3 TREATMENTS FOR COCAINE-SEEKING BEHAVIOR The final section of this chapter will discuss methods of reducing cocaine seeking, particularly via the targeting of

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motivate cocaine seeking in the absence of cocaine, and are especially relevant for understanding the reappearance of drug-taking behavior in drug-abstinent individuals. In general, cocaine cues appear more important in motivating cocaine-maintained behavior than food cues are in motivating food-maintained behavior (Ciccocioppo, MartinFardon, & Weiss, 2004; Spear & Katz, 1991; Weissenborn, Yackey, Koob, & Weiss, 1995). This fits well with observations in humans that cocaine cues are exceptionally strong motivators of cocaine seeking, commanding high rates of responding in the absence of cocaine availability (Panlilio et al., 2005). Studies comparing the ability of cocaine cues and food cues to reinstate reinforcer seeking suggest cocaine cues are exceptionally effective and persistent in this regard (Ciccocioppo et al., 2004). Reinstatement procedures are a unique group of methods useful for modeling drug relapse. Following extinction, cocaine seeking is reliably reinstated by cocaine priming, stress, and cocaine cues (Venniro, Caprioli, & Shaham, 2015). Stress can reinstate both cocaine and food seeking, although more robustly for cocaine (Ahmed & Koob, 1997). Stress-induced reinstatement is difficult to capture as stress may interfere with appetite (Nair, Gray, & Ghitza, 2006; Tunstall & Kearns, 2013). Cocaine and food seeking both can be reinstated by priming, although priming is generally reinforcer-specific (Tunstall & Kearns, 2013; Weissenborn et al., 1995). A recent choice experiment in rats demonstrates the superiority of cocaine cues over food cues in reinstating reinforcer-seeking behavior (Tunstall & Kearns, 2014). In this experiment, rats demonstrated a preference for food when the alternatives were offered in mutually exclusive choice. However, when tested for cue preference in the absence of cocaine or food, the cocaine cue engendered more responding than the food cue, and this effect persisted to at least 8 weeks (Fig. 41.3; Tunstall & Kearns, 2014). Complimentary findings have been observed in a model of “self-imposed abstinence,” where despite the fact that rats selfadministered food to the exclusion of methamphetamine, rats demonstrated enhanced cue-induced methamphetamine seeking over time (Caprioli et al., 2015). Future research is needed to determine how cocaine cues are able to generate preferential seeking of a nonpreferred reinforcer. If cues associated with stimulant drugs have properties that invigorate reinforcer seeking in ways food cues do not, this could cause a bias toward drug-seeking despite the availability of otherwise preferred alternatives.

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FIGURE 41.3 Rats reinstate more to a cocaine cue than a food cue despite opposite preference between reinforcers. Mean total responses ( 6 SEM) on cocaine and food levers during the last day of extinction and on 2-h cue-induced reinstatement tests, administered the next day, 3 weeks, and 8 weeks later. The line through each bar shows the composition of total test responses: below the line are responses initiating the 10-s cue, above the line are responses made during cue presentation. Reproduced from Tunstall, B. J., & Kearns, D. N. (2014). Cocaine can generate a stronger conditioned reinforcer than food despite being a weaker primary reinforcer. Addiction Biology. http://dx.doi.org/10.1111/ adb.12195 [e-pub ahead of print] with permission from Wiley.

cocaine cues. The authors have focused their research efforts on the development of such methods and this section will serve as a review of relevant findings from this work. Counterconditioning is a method that attempts to turn appetitive cues into aversive cues by pairing them with an aversive US. Tunstall, Verendeev, and Kearns (2012) investigated within a rat model whether counterconditioning might be a viable method for reducing cocaineseeking behavior controlled by cues. Rats were first trained to self-administer cocaine during presentations of tone and light cues. Rats could earn cocaine infusions by pressing a lever when either cue was present, but not in their absence. After these cues were established as discriminative cues that reliably occasioned cocaine seeking, the light was subjected to a counterconditioning treatment in one group of rats. Now, lever pressing during the light no longer resulted in cocaine infusions; instead, each light presentation ended with delivery of brief electric footshock. The tone was not presented during this phase. The control group was treated similarly except presentations of the light did not end in footshock. Rats quickly learned the new contingency that the light signaled, as evidenced by a rapid cessation of cocaine seeking during the light in the counterconditioning group as opposed to the control group (Fig. 41.4, left). A stimulus-compounding test was conducted in the absence of cocaine or footshock to test the efficacy of the treatment. This entailed presenting the light simultaneously with the tone (an untreated cocaine cue). Interestingly, the counterconditioning group began

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FIGURE 41.4 Counterconditioning suppresses cocaine-seeking only during active treatment. Left panel: Mean (6SEM) response rates to light over six sessions of the treatment phase for extinction and counterconditioning groups. There were 10 trials per session. Right panel: Mean (6SEM) response rates to the tone-plus-light compound (TL) on two-trial blocks of the stimulus-compounding test for extinction and counterconditioning groups. Reproduced from Tunstall, B. J., Verendeev, A., & Kearns, D. N. (2012). A comparison of therapies for the treatment of drug cues: Counterconditioning vs. extinction in male rats. Experimental and Clinical Psychopharmacology, 20(6), 447 453 with permission from the American Psychological Association.

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FIGURE 41.5 Deepened extinction of cocaine cues. Mean ( 6 SEM) response rates in stimuli X and Y (both signaled cocaine availability) during the first and final sessions of extinction, three AX compound extinction sessions (A is an extinguished cocaine cue; Y was presented alone), and the spontaneous recovery test. *p , 0.05. Reproduced from Kearns, D. N., Tunstall, B. J., & Weiss, S. J. (2012). Deepened extinction of cocaine cues. Drug and Alcohol Dependence, 124(3), 283 287 with permission from Elsevier.

responding in the absence of counterconditioning treatment, exerting as much cocaine-seeking effort as the control group over the course of the test (Fig. 41.4, right). These results suggest only a temporarily suppressive effect of counterconditioning. Kearns, Tunstall, and Weiss (2012) investigated whether the deepened extinction technique, established by Rescorla (2006), could be used to enhance the extinction of cocaine cues. Rats were first trained to self-administer cocaine by pressing a lever during the presentation of cues A, X, and Y (a light, a tone, and a click). Next, each of the cues was extinguished individually. In the deepened extinction treatment phase, cues A and X were

presented simultaneously during additional extinction trials. Cue Y, the standard extinction control stimulus, continued to be presented individually for an equivalent number of additional extinction trials. Combining stimuli A and X produced a spike in cocaine seeking during these additional AX extinction trials, whereas responding remained low to stimulus Y (Fig. 41.5). To test for the effectiveness of the deepened extinction treatment vs. the standard extinction treatment, stimuli X and Y were presented separately on a test for spontaneous recovery one week after the final extinction session. As Fig. 41.5 illustrates, there was significantly less spontaneous recovery to stimulus X (received deepened extinction) than to stimulus Y (received standard extinction; for similar results, see Janak & Corbit, 2011). These results suggest that extinction-based cue treatments like cue-exposure therapy (for review, see Conklin & Tiffany, 2002) may be improved by applying the deepened extinction technique to make the extinction of problematic cocaine cues more lasting. In a follow-up study, we investigated whether combining nondrug appetitive cues with cocaine cues during extinction would also effectively reduce spontaneous recovery of cocaine seeking. If so, this could make clinical application of deepened extinction more feasible. Tunstall, Verendeev, and Kearns (2013) conducted deepened extinction by combining an extinguished cocaine cue (stimulus X) with a previously extinguished food cue (stimulus A) during a phase of additional extinction trials. Presentation of the AX compound resulted in the same spike of reinforcer-seeking behavior that was observed when two cocaine cues were combined (Kearns et al., 2012). However, deepened extinction was not observed. Instead, on the test for spontaneous recovery, there was

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FIGURE 41.6 Outcome specificity in deepened extinction. Mean ( 6 SEM) response rates in stimuli X and Y (both signaled cocaine availability) during three sessions of extinction, the AX compound extinction session (A is an extinguished food cue; Y was presented alone), and the spontaneous recovery test. *p , 0.05. Reproduced from Tunstall, B. J., Verendeev, A., & Kearns, D. N. (2012). A comparison of therapies for the treatment of drug cues: Counterconditioning vs. extinction in male rats. Experimental and Clinical Psychopharmacology, 20(6), 447 453 with permission from Elsevier.

actually greater recovery of cocaine seeking to the cue (X) that was compounded with a food cue during extinction than to a control cocaine cue (stimulus Y) that was always extinguished on its own (Fig. 41.6). In this case, it appeared that the compounding of X with A had formed an association between X and A, such that when X (the cocaine cue) was presented on its own during the test for spontaneous recovery, the memory of A (the food cue) was retrieved, leading to an increase in lever pressing. This result suggests that it could be difficult to use this variant of the deepened extinction procedure in the clinic. In conclusion, measuring the ability of cocaine to reinforce behavior and motivate cocaine-seeking requires careful analysis. We have covered a range of measures that capture different aspects of cocaine-reinforced behavior in the hopes that this may help to better understand mechanisms underlying addiction-like behavior. We have discussed several avenues for development of treatments to reduce the power of cocaine cues over cocaine-seeking behavior. Ultimately, we hope it is possible to develop interventions that disrupt pathological processes that give rise to addictive behavior. This is a difficult aim, but is necessary to assist drug-addicted individuals in ceasing cocaine consumption and preventing relapse.

ACKNOWLEDGMENTS The authors thank NIDA Media Services for figure reproductions. Preparation of this chapter was supported in part by NIH grant DA037269. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Price: The cost (e.g., in effort) of reinforcement. Counterconditioning: pairing an appetitive or aversive stimulus with an outcome of opposite valence. Demand: Willingness to “work” for reinforcement. Demand is considered elastic when it rapidly decreases with increases in reinforcer price. Demand is inelastic when it decreases less rapidly than increases in reinforcer price (i.e., consumption is defended). Demand curve: Consumption of a reinforcer plotted as a function of price. Extinction: Presentation of a cue without its previously associated unconditioned stimulus or reinforcer; discontinuation of reinforcement for a previously reinforced response. Cocaine-seeking behavior: Exerting responses to obtain access to cocaine reinforcement. Fixed-ratio (FR) schedule: A schedule of reinforcement where a certain number of responses must be made to obtain reinforcement (e.g., FR-1, where one lever press results in reinforcement). Progressive-ratio (PR) schedule: A schedule where the number of responses required for the next reinforcer increases progressively (e.g., a response requirement sequence of 1, 2, 4, 8, 16, 32, 64, 128). Seeking taking chain: A procedure where fulfillment of a response requirement on one operant manipulandum (e.g., a lever) causes the presentation of a second manipulandum. The reinforcer is only delivered when the response requirement is met on the second manipulandum. Reinstatement: The reappearance of a previously extinguished response. Cocaine-seeking behavior is reliably reinstated by cocaine priming, stress, and cocaine-associated cues. Reinforcer: A consequence of a behavior that causes that behavior to increase in frequency or probability. Consummatory response: The end response in a chain of reinforcer-motivated behaviors (e.g., eating food).

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