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. Author manuscript; available in PMC: 2013 Jun 1.
Published in final edited form as: Pharmacol Biochem Behav. 2012 Mar 9;101(4):575–580. doi: 10.1016/j.pbb.2012.03.004

Rimonabant Eliminates Responsiveness to Workload Changes in a Time-Constrained Food-Reinforced Progressive Ratio Procedure in Rats

Julie A Marusich 1, Jenny L Wiley 1,2
PMCID: PMC3387812  NIHMSID: NIHMS363478  PMID: 22425597

Abstract

Despite its propensity to increase motivation for food consumption, marijuana use in humans has been associated with “amotivational syndrome.” This “amotivational syndrome” can be characterized by a reduction in response persistence in tasks requiring sustained, but not maximal, effort. To examine this hypothesis, dose-effect functions for THC (0.03–10 mg/kg) and rimonabant (0.1–10 mg/kg) were first determined under a time-constrained PR 5 schedule. During the second phase of the study, doses of THC and rimonabant that did not affect the responses/total reinforced responses were chosen for further evaluation in a series of PR schedules with step sizes of PR 3, PR 5, PR 10, and PR exponential. THC and rimonabant produced decreases in responses per reinforcer, and response rate when behavior was maintained on a PR 5. Rimonabant also decreased session length. During the PR step size manipulation phase, rimonabant decreased responses/total reinforced responses, response rate, and session length, whereas THC only decreased response rate. These results are consistent with previous literature demonstrating that rimonabant decreases motivation for food both in cases where it is earned, as well as under free-feeding conditions, whereas the effects of cannabinoid agonists such as THC on responding for food exhibit greater dependence upon motivational and non-motivational factors, including workload and duration of the task.

Keywords: THC, rimonabant, progressive ratio, rat, step size

Cannabinoids have been found to affect a variety of biological processes including locomotor behavior (Drews et al. 2005), memory (Hampson and Deadwyler 1998), appetite, and food intake (Chaperon and Thiebot 1999; Higgs et al. 2005; Williams et al. 1998). Agonists at the cannabinoid (CB1) receptor in the brain have been shown to increase food intake in rodents and humans (Foltin et al. 1988; Hao et al. 2000; Williams et al. 1998), whereas CB1 antagonists have been found to decrease food intake (Riedel et al. 2009; Wiley et al. 2005a). Rimonabant, a CB1 antagonist, was found to be an effective treatment for obesity in humans (Gelfand and Cannon 2006), and underwent clinical trials (Fernandez and Allison 2004), although it was withdrawn when it was found to produce depression and suicidality in some patients (Traynor 2007). Hence, compounds that are active at the CB1 receptor are likely to alter motivation to obtain food through their effects on appetite, through alteration of hedonic aspects of eating, or both (Cota et al. 2006; Kirkham 2009).

Despite its propensity to increase motivation for food consumption, marijuana use in humans has also been associated with “amotivational syndrome,” meaning that people who use marijuana regularly become more passive and more introverted, and develop personality characteristics suggesting that they generally lack motivation (McGlothlin and West 1968). Behaviors commonly seen in a clinical setting among people who have developed amotivational syndrome from using marijuana include lack of concern, decreased ambition, and fewer goal-driven behaviors (Maugh 1974). This pattern of behavior was observed to be most severe for people who had been using marijuana the longest, and ceased when the individuals discontinued marijuana use (Maugh 1974). While amotivational syndrome has been observed clinically, laboratory research with humans has not shown evidence for marijuana-induced amotivational syndrome in regular users of marijuana (Foltin et al. 1990; Foltin et al. 1989a). Occasional users of marijuana, however, show decreased motivation in a task reinforced by money at low pay rates, but not at higher pay rates (Cherek et al. 2002), suggesting that nonpharmacological factors may modulate marijuana’s effects on motivation.

Previous research has commonly used progressive ratio (PR) schedules of reinforcement to examine motivation to respond for a particular reinforcer, such as food (Hodos 1961), electrical brain stimulation (Hodos 1965) and drugs (Richardson and Roberts 1996; Stafford et al. 1998). This type of schedule increases the response requirement for the reinforcer after each time a reinforcer is earned. Often, this increase in response requirement is made exponentially (1, 2, 4, 6, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, etc.) (Richardson and Roberts 1991), but it can also be increased additively (5, 10, 15, 20, 25, etc.) (Higgs et al. 2005; Wiley and Compton 2004). When using a PR schedule, the reinforcing effect of a particular stimulus is evaluated by the breakpoint, defined as the ratio at which point the subject stops responding for the reinforcer (Arnold and Roberts 1997), this measure may not be the most relevant measure for all PR studies. For example, reinforcing efficacy may not be a unitary concept (Bickel et al. 2000) and factors other than reinforcing efficacy can also produce changes in breakpoint (Richardson and Roberts 1991; 1996; Stafford et al. 1998). One type of procedure, in which an alternative measure of reinforcer efficacy might be appropriate, is time-constrained PR responding (e.g., Aberman et al. 1998; Mobini et al. 2000). Under this type of schedule, the session ends after a fixed amount of time even if a long pause in responding (i.e., breakpoint) has not occurred. Although less commonly used, an advantage of time-constrained schedules is that session duration tends to be more similar to that used in other investigations of drug effects on operant responding for food reinforcement (Aberman et al. 1998). In addition, factors such as fatigue and satiation may be less likely to influence responding. As noted, however, a disadvantage of time-constrained schedules is that a true breakpoint may not be reached. A more accurate assessment of the subject’s motivation to work under conditions requiring sub-maximal effort might be the ratio of responses/total reinforced responses (i.e., the cost of the reinforcer).

Whereas the ratio value at each step is a measure of the work required to earn a specific reinforcer, the step size reflects the amount of work that is required to continue receiving reinforcers throughout the session. Hence, to earn the same number of reinforcers, a rat must show more sustained effort over a session with a larger step size than during one with a smaller step size. Drugs that interfere with this sustained effort through effects on motoric or motivational processes (e.g., marijuana-induced amotivational syndrome) might be expected to produce greater deficits in responding at higher workloads. Given the presumed effects of cannabinoids on motivational processes related to food as well as other reinforcers in humans, as described above, the underlying hypothesis of this study was that Δ9-tetrahydrocannabinol (THC), the primary psychoactive substituent of marijuana (Gaoni and Mechoulam 1964), might contribute to a putative marijuana-induced amotivational syndrome through a reduction in response persistence in tasks requiring sustained, but not maximal, effort. To examine this hypothesis, dose-effect functions for THC and rimonabant were first determined under a time-constrained PR 5 schedule. During the second phase of the study, doses of THC and rimonabant that did not affect the responses/total reinforced responses ratio were chosen for further evaluation in a series of PR schedules with different step sizes. If THC selectively affects motivation for food in tasks requiring greater overall effort, we would expect to see lower responses/total reinforced responses (compared to vehicle) at increased workloads that might not occur in tasks requiring less effort.

Methods

Subjects

Twelve male Sprague-Dawley rats (Harlan, Dublin, VA) were individually housed in clear plastic cages in a temperature-controlled (20–22°C) environment with a 12 hr light-dark cycle (lights on at 7 a.m.). During acquisition and testing under the progressive ratio procedure, rats were maintained at 85% of their free feeding weight in order to motivate them to consume the food pellet reinforcers. Rats had ad libitum access to water in their home cages at all times. The studies reported in this manuscript were carried out in accordance with guidelines published in the Guide for the Care and Use of Laboratory Animals (National Research Council 1996) and were approved by the Institutional Animal Care and Use Committee at Virginia Commonwealth University.

Apparatus

Rats were trained and tested in standard operant conditioning chambers (Lafayette Instruments Co., Lafayette, IN) housed in sound-attenuating cubicles. Each chamber had three retractable levers, only one of which (the left) was used for this study. Pellet dispensers delivered 45-mg Bio Serv (Frenchtown, NJ) sucrose pellets to a food cup in the middle of the front wall of the chamber between two of the response levers (right lever retracted) and over the third (retracted) center lever. Fan motors provided ventilation for each chamber and masked extraneous noise. House lights located above the food cup were illuminated during training and testing sessions. A micro-computer with Logic ‘1’ interface (MED Associates, Georgia, VT) and MED-PC software (MED Associates) was used to control schedule contingencies and to record data.

Procedure

Rats initially were trained to lever-press for food reinforcement on a fixed ratio 1 (FR 1) schedule of reinforcement. Once lever pressing was acquired (2–3 days), a progressive ratio 5 (PR 5) schedule was instituted. Under this schedule, rats had to press the lever 5 times in order to receive the first food pellet. For each subsequent reinforcer, the ratio requirement was increased by 5 (i.e., 5, 10, 15, etc.) until the rat failed to respond for two min. Failure to respond for two min resulted in session termination. Upon termination of the session following a 2 min pause in responding (i.e., breakpoint), house lights were extinguished, the lever was retracted, and the rat remained in the chamber until 30 min had passed from the start of the session. When rats continued to lever press without pausing for at least 2 min throughout the session, the maximum session duration was 30 min, at which point the house lights were extinguished and the lever was retracted.

Daily (Monday-Friday) training sessions continued until responding on the PR 5 schedule was stable (approximately 3 months). Subsequently, drug testing was initiated. Drug tests typically occurred on Tuesdays and Fridays, with continued training on Mondays, Wednesdays, and Thursdays. For each dose-effect curve determination, doses (including saline) were administered in a random order according to a modified Latin square design. Drugs investigated were THC (0, 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg) and rimonabant (0, 0.1, 0.3, 1, 3, and 10 mg/kg). All subjects were administered each dose of each drug once. The rats were also tested with methanandamide, nicotine and diazepam (data not included in this study).

Following investigation of the effects of pharmacological challenges, manipulation of the step size in the increase of the ratio with each successive reinforcer was altered, using the same subjects as in the previous phase. For this manipulation, the initial fixed ratio was 5, and the step increase was varied additively, with step sizes of 3 (PR 3), 10 (PR 10), or exponential steps (e.g., 2X2, 3X3, 4X4, 5X5, etc; PR Ex). Subjects were exposed to these new step sizes on test days only. Again, drug testing occurred on Tuesdays and Fridays. For all rats, saline was assessed first and was examined during PR 5, PR 3, PR 10, and PR Ex in consecutive order. Subsequently, 3 mg/kg rimonabant was tested in all step sizes in the same order as for saline, followed by tests with 3 mg/kg THC at all step sizes.

Drugs

THC (National Institute on Drug Abuse, Rockville, MD) and rimonabant (NIDA) were suspended in a vehicle of absolute ethanol, Emulphor-620 (Rhone-Poulenc, Inc., Princeton, NJ), and saline in a ratio of 1:1:18. This vehicle has been used previously, and the ethanol content is not sufficient to produce behaviorally meaningful effects (Wiley et al., 2005a; Wiley et al., 2005b; Wiley et al., 2006). Both drugs were administered to the rats intraperitoneally at a volume of 1 ml/kg. Saline was used as a comparison. Pre-session injection times were based upon our previous experience with these compounds and were as follows: 30 min for THC and saline and 40 min for rimonabant.

Data Analysis

Three dependent variables are reported: responses/total reinforced responses, response rate, and session length. Responses/total reinforced responses was calculated as the number of responses divided by the number of pellets earned during the session. Response rates were calculated as number of responses divided by actual session duration, which varied based on when rats stopped responding for 2 min (i.e., reached a breakpoint). Since breakpoint could be reached either by a 2 min delay in responding or by responding without lengthy pause for 30 min, this measure is not included in the graphical data presentation; however, the percentage of rats that actually reached a breakpoint (vs. those that responded throughout the 30 min session) was analyzed through use of Cochran Q tests across doses (for dose-effect curve) and across step sizes for each drug in the second part of the study (Siegel and Castellan 1988). Session length was the amount of time (s) the rat was in the chamber and responding with pauses of less than 2 min. Maximum session length was 1800 s. One way repeated measures analyses of variance (ANOVAs) with dose as the within subjects factor were used to analyze dependent variables for each drug. Two-way repeated measures ANOVAs (drug x step size) were used to analyze dependent variables for the experiments in which manipulation of step size occurred. Following significant ANOVAs, Tukey post hoc tests were used to determine differences between means. All tests were considered significant at p < 0.05.

Results

For the purposes of this study, breakpoint was defined as the ratio immediately preceding a pause in responding that lasted for 2 min. If a rat did not pause for at least 2 min during the session, a true breakpoint was not achieved. Table 1 shows the percentage of rats, for which a breakpoint was observed. Statistical analysis of these distributions for the dose-effect curves revealed that the frequencies of rats that paused for at least 2 min during the session differed across dose for THC [Q (6) = 17.8, p<0.05], but not for rimonabant [Q (5) = 8.8, p>0.05]. In contrast, percentages for THC did not differ across step size [Q (3) = 6.3, p>0.05] whereas they did for rimonabant [Q (3) = 24, p<0.05] and saline [Q (3) = 11.9, p<0.05]. A greater number of rats treated with rimonabant or saline, but not with THC, ended the session early with step sizes of PR 5, PR 10, and PR Ex than under a PR 3 schedule.

Table 1.

Percentage of rats with 2 min pauses in responding (breakpoints) during 30 min session.*

Dose-Effect Curves
THC** Rimonabant**
Dose (mg/kg) % Paused Dose (mg/kg) % Paused
0 83 0 58
0.03 92 0.1 75
0.1 83 0.3 50
0.3 75 1 67
1 50 3 75
3 25 10 92
10 75
Step Size Manipulation
Step Size Saline** % Paused THC % Paused Rimonabant** % Paused
PR 3 0 0 0
PR 5 50 25 100
PR 10 63 25 100
PR Ex 75 38 100
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*

n = 12 for dose-effect curves and n = 8 for step size manipulation.

**

Significant differences noted across dose (top) or step size (bottom) for the indicated treatment condition.

For the dose-effect assessment, Figure 1a shows effects of THC and rimonabant on responses/total reinforced responses. Larger doses of THC and rimonabant produced decreases in this measure. Both drugs showed a significant effect of dose [THC: F (6, 66) = 8.32, p < 0.05; rimonabant: F (5, 55) = 8.10, p < 0.05], with 10 mg/kg of both drugs producing significant decreases in the responses/total reinforced responses ratio as compared to saline.

Figure 1.

Figure 1

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Panels on the left side of the figure show the effects of THC and rimonabant (SR) on responses/total reinforced responses (panel A), response rate (panel B) and session duration (panel C) during a time-constrained PR 5 schedule. Panels on the right side of the figure show the effects of saline, THC, and rimonabant (SR) on responses/total reinforced responses (panel D), response rate (panel E) and session duration (panel F) during time-constrained progressive ratio schedules, with varying PR requirements (PR 3, PR 5, PR 10, and PR Exponential). Values shown are means (± SEM) for 12 rats (left panels) or 8 rats (right panels). Asterisks indicate significant difference from saline in the left panels, whereas in the right panels, asterisks indicate a significant drug X schedule interaction and posthoc difference of drug effect compared to saline within the same schedule. Pound signs indicate significant drug X schedule interaction and posthoc difference of schedule compared to PR 5 schedule with the same drug (right panels). Dollar signs indicate a significant main effect of rimonabant on the responses/total reinforced responses measure as compared to saline (panel D). At signs (@) indicate a significant main effect of the PR Ex schedule as compared to PR 5 and PR 3 schedules (panel D). All significant differences are based upon ANOVA followed by Tukey post hoc tests, as appropriate (p<0.05).

Figure 1b shows effects of THC and rimonabant on response rate. Larger doses of both cannabinoids produced decreases in response rate. THC showed a significant effect of dose on response rate [F (6, 66) = 12.92, p < 0.05], with 3 mg/kg and 10 mg/kg producing significant decreases as compared to saline. Rimonabant also showed a significant effect of dose on response rate [F (5, 55) = 6.77, p < 0.05], with 10 mg/kg producing significant decreases compared to saline.

Figure 1c shows effects of THC and rimonabant on session duration. While none of the doses of THC significantly altered the session length compared to saline, 10 mg/kg rimonabant produced a significant decrease in the amount of time the rats spent responding before pausing for 2 min [F (5, 55) = 4.55, p < 0.05].

For the PR step size manipulation, Figure 1d shows mean responses/total reinforced responses (±SEM) at each PR step size under effects of each pharmacological challenge. The responses/total reinforced responses ratio increased as the step size increased across pharmacological challenges, and higher ratios were always reached following saline administration than following rimonabant administration. An ANOVA showed there was a significant main effect of PR size on responses/total reinforced responses ratio [F (3, 21) = 9.09, p < 0.05], a significant main effect of pharmacological challenge [F (2, 14) = 11.33, p < 0.05], but no significant interaction. Posthoc tests revealed a significant decrease in responses/total reinforced responses ratio for rimonabant compared to saline, collapsed across all step sizes, and a significant increase in this ratio during the PR 10 and PR Ex schedules as compared to during the PR 3 and PR 5 schedules, collapsed across pharmacological challenges.

Figure 1e shows the group mean response rate at each PR step size for each pharmacological challenge. Response rate varied little as the PR step size increased, but did vary as a function of pharmacological challenge. For response rate, there was a significant effect of pharmacological challenge [F (2, 14) = 15.65, p < 0.05], no significant effect of step size, and a significant interaction [F (6, 42) = 2.57, p < 0.05]. Posthoc analysis of the interaction revealed that both THC and rimonabant significantly decreased response rates compared to saline at each of the step sizes.

Figure 1f shows the effects of saline, THC and rimonabant on session length at each PR step size. Significant effects were observed for pharmacological challenge [F (2, 14) = 16.65, p < 0.05], step size [F (3, 21) = 16.42, p < 0.05], and the interaction [F (6, 42) = 6.32, p < 0.05]. Posthoc analysis of the interaction revealed that, at the lowest PR 3 value, session length was close to maximum (15 min) for saline, and neither drug altered session duration. Session length was significantly longer for saline and rimonabant at PR 3 compared to PR 5, whereas THC did not significantly affect session length at any of the PR values as compared to PR 5. Rimonabant significantly decreased session length as compared to saline at step values of PR 5, PR 10 and PR Ex, whereas THC did not.

Discussion

Results of the acute dose-effect curve determinations in the present study show that THC and rimonabant produce similar patterns of effects, in that, higher doses of each drug decreased response rates as well as the amount of work that rats perform for each reinforcer (responses/total reinforced responses). These data are in agreement with a large body of previous work showing that THC and other psychoactive cananbinoid agonists dose-dependently decrease food-reinforced responding in operant procedures using FR schedules (Carriero et al. 1998; Dykstra et al. 1975), and that rimonabant also decreases responding (De Vry and Jentzsch 2004; De Vry et al. 2004; McLaughlin et al. 2003). In contrast, previous research examining effects of cannabinoids on responding in rodents for food under PR schedules with less restrictive session times has shown inconsistent effects. Whereas THC, CP55,940, and the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) increased breakpoints in PR schedules (Higgs et al. 2005; Solinas and Goldberg 2005; Wakley and Rasmussen 2009; Ward and Dykstra 2005), the synthetic cannabinoid agonist WIN 55,212-2 decreased breakpoint when administered acutely to adult rats (Drews et al. 2005). If the current PR task had been less time restrictive, the dose-dependent decrease in pausing following THC treatment would be consistent with breakpoint increases. Therefore, the present results would likely be consistent with previous literature on effects of THC on less time restricted PR schedules (Higgs et al. 2005; Solinas and Goldberg 2005). Rimonabant has consistently been shown to decrease breakpoint in rats (Solinas and Goldberg 2005; Wakley and Rasmussen 2009; Ward et al. 2008). [Although not calculated, changes in response cost of each reinforcer (i.e., responses/total reinforced responses) in each of these previous studies would have directly paralleled changes in breakpoint.] Hence, the results presented here appear more comparable to those of other time-constrained FR operant schedules than to those from PR tasks, with both agonists and antagonists decreasing responding at higher doses.

To explore further the effects of increased workload on responding in a time-constrained PR paradigm, manipulation of the step size of the PR schedule was undertaken. Probe doses of 3 mg/kg THC and 3 mg/kg rimonabant did not affect responses/total reinforced responses ratios or session length during the original dose-effect curve determination. While 3 mg/kg rimonabant also did not affect response rate, 3 mg/kg THC decreased response rate in the initial dose-effect testing. Increase in the workload through use of PR 10 and PR Ex schedules was accompanied by an overall increase in the responses/total reinforced responses for each reinforcer compared to the training PR 5 schedule (main effect of schedule); however, the increase across schedules for rimonabant-treated rats was less than for saline-treated rats (main effect of drug treatment), suggesting that rats receiving rimonabant expended consistently less effort across varying schedule demands. This interpretation was supported by the observation that rimonabant-treated rats also had lower response rates in all schedules and shorter session durations for all but the PR 3 schedule. Further, all of the rimonabant-treated rats reached a true breakpoint during sessions with workloads PR 5 and greater, suggesting an overall suppressive effect of rimonabant on motivation to work for food.

Pharmacological history of the rats may also have played a role in this effect. Although values for the three dependent measures were similar for saline and 3 mg/kg THC during both phases of the study, 3 mg/kg rimonabant, a dose that did not affect responses/total reinforced responses or response rates during the rimonabant dose-effect curve determination, suppressed both of these measures during the second phase of the study. Since rimonabant was tested at all step sizes after saline, but before THC, an overall shift in baseline values for these measures is not a likely explanation for these results. Rather, the decreases appear to be selective for rimonabant treatment. Together, these findings are consistent with previous research suggesting that rimonabant and its analogs decrease both breakpoints under PR schedules (Solinas and Goldberg 2005; Ward and Dykstra 2005; Ward et al. 2008), and food intake in free-feeding paradigms (Chaperon and Thiebot 1999; Gelfand and Cannon 2006; Wiley et al. 2005a). Further, the fact that rimonabant-treated rats showed a generalized attenuation of interest in food across tasks that appeared to strengthen with a history of occasional use is intriguing in light of its removal from the market due to its association with suicidality and depressive symptoms following repeated use (Traynor 2007).

In contrast, THC-treated rats showed equivalent work expenditure for each reinforcer (responses/total reinforced responses) and persisted in responding for as long a duration as saline-treated rats under each PR schedule, despite consistently responding slower (i.e., decreased response rates). Further, similar to the saline-treated rats, they exhibited increases in the number of responses emitted for each reinforcer at heavier workloads. The fact that THC-treated rats persisted in responding across the session and actually worked more when the task required greater effort for reinforcement suggests that non-motivational factors (e.g., motor impairment, time perception alterations) may account for decreases in responding produced by THC. Hence, consistent with the increased breakpoints observed for THC in previous food-reinforced PR studies in rats (Higgs et al. 2005; Solinas and Goldberg 2005; Wakley and Rasmussen 2009), the present results also do not support a generalized decrement in motivation for food reward following THC administration. Rather, they are consistent with laboratory studies in humans that have failed to find a THC-induced amotivational effect (Foltin et al. 1990; Foltin et al. 1989b).

In summary, the present experiment found that, when behavior was maintained on a PR 5 schedule, higher doses of THC and rimonabant produced decreases in the amount of work rats performed to receive a reinforcer, an effect that was accompanied by decreases in overall response rate. During the PR step size manipulation phase, 3 mg/kg rimonabant, a dose that did not alter responding during the acute dose-effect curve determination, suppressed responses/total reinforced responses and response rate across all levels of PR step size. Further, session duration was decreased at PR 5 and above, resulting in all animals achieving an actual breakpoint (2 min pause in responding). In contrast, THC-treated rats showed a decrease only in response rate, and worked harder for each reinforcer as workload increased from PR 5. These results are consistent with previous literature demonstrating that rimonabant decreases motivation for food both in cases where it is earned, as well as under free-feeding conditions, whereas the effects of cannabinoid agonists such as THC on responding for food exhibit greater dependence upon motivational and non-motivational factors, including workload and duration of the task.

Highlights.

  • The purpose was to examine effects of THC and rimonabant on progressive ratio schedules.

  • THC and rimonabant decreased responses/total reinforced responses and response rate.

  • PR maintained behavior is sensitive to effects of cannabinoids.

  • Rimonabant decreases motivation for food when it is earned, or under free-feeding conditions.

  • THC exhibits greater dependence upon workload and duration of the task.

Acknowledgments

Research supported by NIH/NIDA Grants DA-03672 and DA-016644. The authors thank Timothy Lefever for comments on an earlier version of this manuscript.

Footnotes

The authors have no conflicts of interest.

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