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Effects of Levamisole on Cocaine Self-Administration by Rats.

The Drug Enforcement Administration was the first organization to report the presence of levamisole (LVM) as a cutting agent in illicit cocaine (Valentino & Fuentecilla, 2005). Since this initial report, others have repeatedly found LVM in illicit cocaine (Abdul-Karim, Ryan, Rangel, & Emmett, 2013; Casale, Corbeil, & Hays, 2008) and also in heroin (Casale & Casale, 2011). In 2009, the United States Substance Abuse and Mental Health Services Administration indicated that over 70% of seized bulk cocaine samples tested positive for the presence of LVM. Overall, LVM accounted for roughly 6% of the bulk product sold as cocaine (Casale et al., 2008), indicating that its addition occurs early in the drug production and sales process rather than at the street sales or street use level. The primary intended use of LVM was for treating parasitic worm infections, although its subsequent clinical use was expanded to include the treatment of colon cancer (Amery & Bruynseels, 1992). LVM was withdrawn from the U.S. market in 2000 due to reports indicating serious side effects in humans (e.g., agranulocytosis, vasculitis, and leukoencephalopathy; Abdul-Karim et al., 2013; Formeister, Falcone, & Mair, 2015; Hoftnaier et al., 2014; Knowles et al., 2009; Michaud et al., 2014) and the availability of newer, safer replacement drugs.

LVM is a white crystalline ("snow-like") bulk material, and its presence in what is sold as cocaine cannot be detected by visual inspection. But appearance alone is unlikely to account for the common use of LVM as an adulterant because other, less expensive alternatives (e.g., caffeine, talc, lidocaine) are readily available. It seems more likely that the pharmacological effects of LVM are somehow responsible because the drug is a nicotinic receptor agonist that also inhibits dopamine and norepinephrine reuptake, resulting in weak stimulant effects (Adams, 1978; Hofmaier et al., 2014; Jimenez-Gonzalez, Ros-Moreno, Moreno-Guzman, & Rodriguez-Caabeiro, 1998; Robertson, Bjorn, & Martin, 1999). It is possible that adding LVM to cocaine increases the amount of cocaine purchased by street users or the amount they are willing to pay for a given quantity, either of which would be desired outcomes from the perspective of those who produce and distribute cocaine. There is, however, no empirical support for either possibility.

Two recent behavioral studies do provide evidence that LVM and cocaine can interact synergistically. One study, with planaria, demonstrated that both LVM and cocaine increased stereotyped movements and that the two drugs interacted synergistically when combined (Tallarida et al., 2014). Cocaine, but not LVM, produced conditioned place preference, and combining a submaximal dose of cocaine with LVM again indicated a synergistic interaction (Tallarida et al., 2014). Similar results were obtained in a study with rats (Tallarida, Tallarida, & Rawls, 2015), which found that LVM sometimes enhanced the rewarding and locomotor effects of low doses of cocaine.

Conditioned place preference is one well-established method for studying the rewarding (or reinforcing) effects of cocaine; drug self-administration is another, more direct method (Panlilio & Goldberg, 2007). The purpose of the present study was to examine whether pretreating rats with LVM increased the amount of cocaine administered in a single bout across a range of cocaine doses. If so, this effect could account for the use of LVM as an adulterant.



Thirty-two male Sprague Dawley rats (Crl:SD) surgically implanted with chronic indwelling jugular catheters (polyurethane with a microrenethane tip; SAI Infusion Technologies, Lake Villa, Illinois) were purchased from Charles River Laboratories (Portage, Michigan). Catheters were inserted into the jugular vein and advanced to the atrium; the exteriorized portion exited a dorsal incision site at the midscapular area and was sutured and secured with a wound clip. Each rat was fitted with a spandex jacket (Lomir Biomedical Inc., Notre-Dame-de-I'ile Perrot, Quebec, Canada) that was used to secure the catheter to a "quick-disconnect" jacket adaptor (SAI Inftision Technologies) located on the dorsal surface of the rat. Rats were approximately four months old (200-400 g) and had previous experience with self-administering intravenous cocaine (approximately three months) and with a novel, proprietary psychoactive compound under conditions equivalent to those used in the present study; all rats had comparable drug histories. A 10-day washout period was imposed prior to initiation of the present study.

Animals were pair-housed in polycarbonate cages (56 x 33 x 21 cm) with nonaromatic bedding. To ensure that both animals had access to food and to minimize the risk of catheter damage during social play, animals were separated by a perforated metal barrier (i.e., Buddy Barrier, American Metal Fab, Three Rivers, Michigan; Boggiano et al., 2008) at all times. This barrier allowed for limited physical contact and interaction (visual, olfactory) between rats. Bedding was changed and cages were sanitized weekly, and animals were provided with both durable (Nyla rod) and nondurable (Aspen wood blocks) enrichment items. Cages were housed within a temperature--(20-26[degrees]C), humidity--(30%-70%), and air pressure-controlled vivarium on a light-dark cycle of 12 h each (fluorescent lights on at 6:00 a.m.). Lab Diet Certified Rodent Diet #5002 (PMI Nutrition International, Inc., Shoreview, Minnesota) was provided throughout the study, and animals were allowed ad libitum access to water via bottles affixed to the outside of each cage. All experimental procedures and husbandry practices received prior approval from an institutional animal care and use committee and were conducted in full compliance with current national and international laws and in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011).

Prior to every session, the animals' catheters were flushed with 1.0 ml sterile isotonic saline solution (0.9% Normal Sterile Saline for Injection [USP], Baxter Healthcare, Deerfield, Illinois) to ensure smooth, unrestricted flow into the catheter. During the flush, the animal was observed for any signs of exterior or interior catheter leakage (e.g., the presence or development of a subdermal protrusion near the catheter passage from midscapular to right jugular access to the heart). Following session termination, animals were disconnected from the swivel-and-tether system, and their catheters were subsequently locked with either 0.5 ml of a heparinized saline solution (30% heparin) or a heparinized dextrose solution (30% heparin), depending on whether the session immediately preceded a break in the training or testing sequence (i.e., a day off).

Catheters, exteriorization sites, quick-disconnect systems, and jackets were inspected and animals were observed daily for signs of disease or distress. If catheters were found disconnected or otherwise suspected to have been compromised (as indicated by, e.g., lack of responding during cocaine maintenance sessions, observed swelling, unusual difficulty or ease of injection during presession flush), patency was tested using an acute dose of methohexital (0.5 mg/kg; Brevital, Portage Pharmacy, Portage, Michigan) delivered via bolus injection through the catheter, and the animal was subsequently observed for prototypic signs of acute administration of a rapid-onset, short-acting barbiturate (i.e., loss of righting reflex and lack of muscle tone). If the catheter was found nonpatent, that animal was excluded from further testing and was humanely euthanized in accordance with institutional standard operating procedures approved by an institutional animal care and use committee. If a patency check was conducted on an animal and no issue with the catheter was discovered, the animal was given that day off, and training was restarted the following day.


Two-lever operant chambers (30.5 x 24.1 x 21.0 cm; Model ENV-008CT, Med Associates, St. Albans, Vermont), equipped with a swivel-and-tether system, signal lights above each lever, and a source of ambient illumination (house light), were used. Chambers were equipped with both a food hopper for pellet deliveries (response acquisition) and a single-speed (0.735 ml/min) syringe drive infusion pump (PHM-100, Med Associates). A white-noise generator connected to a single external speaker was used to mask the sound of injection deliveries and any extraneous noise. 16 chambers were integrated and controlled through 16 interface modules (DIG-716B, Med Associates) connected to an IBM-based computer system. Experimental events and data collection were controlled through a Med-PC IV software system (Med Associates).

The injection volumes ranged from approximately 35 to 150 |xl/injection. The injection volume was determined by the duration of pump activation, which was controlled via computer software (Med-PC IV, Med Associates). The duration of pump activation was based on the body weight of the animal, which was measured each day immediately prior to the session. Infusion durations ranged from 6.9 to 10.1 s (M = 8.4; SEM = 0.02). Previous research has shown that injection onset and duration may be varied from immediate to 100 s without any significant effect on the acquisition or maintenance of drug self-administration (e.g., Crombag, Ferrario, & Robinson, 2008; Panlilio et al., 1998; Woolverton & Wang, 2004).


Initially, rats were reduced to 85% to 95% of their individual free-feeding body weights to facilitate shaping of the initial lever-press response. Upon initiation of a session, a single retractable lever (left lever) extended into the chamber, and a corresponding stimulus lamp (located directly above the lever) and a house light were illuminated. Initially, lever-press responses were reinforced on a fixed-ratio 1 (FR 1) schedule of food reinforcement (i.e., a 45-mg grain-based Dustless Precision Pellet [Bio-Serv, Flemington, New Jersey] was delivered immediately after each lever press). Sessions terminated after 50 reinforcer (food) deliveries or 30 min elapsed, whichever occurred first. Subsequent training sessions were comparable but progressed with a gradually increasing FR requirement implemented across sessions (e.g., Day 1 : FR 1, Day 2: FR 2, Day 3: FR 3, and so on), which terminated with an FR 5 for all rats.

For the first cocaine training session, upon completion of the FR 5 response requirement, rats received both a single food pellet and an intravenous injection of cocaine (0.56 mg/ kg/injection). Following access to both food and cocaine deliveries in this single session, completing the FR 5 schedule in all subsequent training sessions resulted solely in the delivery of a single bolus of cocaine (0.56 mg/kg/injection). As noted, injection duration times and volumes were based on each individual animal's daily presession body weight, such that each animal received 0.56 mg/kg cocaine injections. Maintenance sessions terminated following delivery of 10 reinforcers (total daily dose of 5.6 mg/kg) or 60 min, whichever occurred first. Sessions were limited to 10 injections to reduce the likelihood of tolerance developing to the reinforcing effects of cocaine over the initial course of training and to prevent the possibility of overdose or toxicity (Gauvin, Guha, & Baird, 2015; Young & Herling, 1986). The 10 drug deliveries (total dose of 5.6 mg/kg) also provided a total daily dose that was within the behaviorally active range for cocaine commonly used in drug discrimination (e.g., Craft & Stratmann, 1996; Lamas, Negus, Gatch, & Mello, 1998) and locomotor activity assays (e.g., Thomsen, 2014).

During injections, the stimulus lamp above the active lever flashed on and off for 0.5 s and the lever was retracted from the chamber. A 10-s time-out followed each injection, during which all lights were extinguished and the lever remained retracted. Following the 10-s time-out, the stimulus and house lights were illuminated and the lever was inserted back into the chamber. Subsequent sessions were comparable but progressed with a gradually increasing FR requirement implemented across sessions, terminating with an FR 10 for all rats. Training sessions were conducted 5 to 7 days each week at approximately the same time each day.

Each rat was required to maintain less than 20% day-to-day variability in the total number of injections earned for three consecutive days prior to each testing sequence. When this criterion was met, a sequence comprising three consecutive daily 1-h sessions began. For LVM test sessions, animals were administered an intraperitoneal injection of LVM (1 or 10 mg/ kg) at a volume of 10 ml/kg 30 min prior to initiating the self-administration session. The pretreatment time was based on previous neurochemical (Spector, Munjal, & Schmidt, 1998) and behavioral data (Tallarida et al., 2014, 2015) showing increased dopamine concentrations and notable behavioral effects 30 min after exposure to LVM. Following the injection, each animal was placed into the darkened chamber until 30 min had elapsed, at which point the test session was initiated. During test sessions, rats were allowed unlimited access to self-administer a dose of cocaine (0-1.0 mg/kg/injection) on an FR 10 schedule of reinforcement for 1 h for three consecutive days. Test sequences always alternated with cocaine maintenance sessions. Substitution tests for saline solution and the maintenance dose (MD; 0.56 mg/kg/injection) for the cocaine-alone condition were conducted for all animals (n = 32) to ensure that proper stimulus control had been established. Every other dose of cocaine was tested with a random subgroup of animals (n = 6). No LVM dose higher than 10 mg/kg was administered due to the known direct cardiotoxic effects of higher doses of LVM and cocaine in the rat (Onuaguluchi & Igbo, 1990). Accordingly, no cocaine dose higher than 0.56 mg/kg/injection was tested with either LVM pretreatment (1 or 10 mg/kg). Testing occurred in the following order: (a) cocaine alone, (b) 1 mg/kg of LVM, and (c) 10 mg/kg of LVM. All doses of cocaine (in all three conditions) were tested in random order.


Cocaine hydrochloride and LVM hydrochloride (Sigma-Aldrich, St. Louis, Missouri) were prepared weekly by dissolving the salt in isotonic saline solution, which was filtered through a 0.22-[micro]m polyvinylidene fluoride filter. Doses were calculated and are expressed as the base. Casale et al. (2008) reported that LVM makes up about 6% of the weight of confiscated shipments of "cocaine"--that is, 1 g of "cocaine" contains 60 mg of LVM. The "standard" cocaine dose established by federal statute sentencing guidelines of the U.S. Congress is 100 mg in a drug-naive user (United States Department of Justice, 2002) and up to 1 g in the experienced user (Chitwood, 1985). The amount of LVM received by a rat at the 1 mg/kg dose is equivalent to a 60 kg person administering 60 mg in 1 g of bulk illicit street product.


Figure 1 displays the group mean total number of injections self-administered across the three sessions of each experimental condition (solid lines) and the number of injections during each 1-h session (bars) for each cocaine dose and the three pretreatment conditions (cocaine alone, 1 mg/kg of LVM, and 10 mg/kg of LVM). During cocaine-alone testing, all doses of cocaine engendered extremely stable day-to-day intake over the three days of access to cocaine (M = 32.19 injections; SEM = 1.71), and responding was maintained across the full tested dose range; even relatively low doses of cocaine (0.018-0.032 mg/kg/injection) maintained stable day-to-day mean intake across the 3-day tests. There were, however, substantial differences across animals in performance at these low doses.

Visual inspection of Fig. 1 suggests that pretreatment with 1 mg/kg of LVM increased the overall day-to-day variability and decreased the number of cocaine injections earned (M = 28.08 injections; SEM = 2.12). Pretreatment with 10 mg/kg of LVM was associated with variable and relatively low levels of self-administration (M- 15.24 injections; SEM = 1.67) across the three days of exposure, regardless of cocaine dose. As suggested by visual comparison, statistical analysis using a one-way repeated-measures analysis of variance (ANOVA; GraphPad Prism 7, La Jolla, California) indicated that LVM at 10 mg/kg significantly decreased the mean number of injections when compared with the cocaine-alone mean, F(2, 17) = 8.09, p = .007. Dunnett's multiple comparison test revealed statistically significant differences (p < .05) for all doses of cocaine when 0- and 10-mg/kg LVM pretreatment conditions were compared, except for the 0.01-mg/kg/injection dose level (p > .05). A repeated-measures ANOVA indicated, however, that 1-mg/kg LVM pretreatment did not significantly reduce the mean number of cocaine selfadministration responses, F(2, 17) = 2.18, p = . 14.

Although the total number of cocaine injections earned in a session is a meaningful dependent variable, it provides no information about the temporal pattern of injections, which is an important dimension of self-administration behavior (Young & Herling, 1986). Therefore, cumulative records for rats administering all doses of cocaine when LVM was and was not administered were carefully compared. Figure 2 shows representative cumulative records depicting one rat's self-administration of 0.56 mg/kg/injection of cocaine when it was pretreated with 0, 1, and 10 mg/kg of LVM. As this figure suggests, the within-session pattern of responding was similar when LVM was and was not administered, although fewer responses typically occurred when LVM was administered, especially at the higher (10 mg/kg) dose. Under all conditions, a relatively large number of responses occurred early in the session, followed by slower and similarly paced responding for the remainder of the session. Although this effect is not apparent in Fig. 2, the within-session pattern of responding was comparable across the 3 days of each pretreatment condition.

To allow for a quantitative analysis of temporal patterns of responding, for each rat the percentage of responses emitted in the first quarter (i.e., 15 min) of each session was calculated. Group mean values for this measure when 0.56 mg/kg/injection of cocaine was self-administered under the three pretreatment conditions are shown in Fig. 3. Analysis using a one-way repeated-measures ANOVA revealed that the percentage of responses emitted during the first quarter of a session did not significantly differ as a function of LVM pretreatment condition, (F(2,31) = 2.27, p = .13). Like visual inspection of cumulative records, statistical analyses of first-quarterof-the-session responding suggest that pretreatment with LVM did not affect the temporal pattern of cocaine self-administration, although under some conditions (i.e., at 10 mg/ kg of LVM and most doses of cocaine) it did reduce the total number of responses emitted.


Two prior studies using a conditioned place preference procedure demonstrated that under some conditions, LVM increased the rewarding effects of cocaine (Tallarida et al., 2014, 2015). Conditioned place preference procedures assess the rewarding value of a drug by determining the amount of time spent in a location historically predictive of the presence of that drug relative to the time spent in a similar, but not predictive, location--a measure often termed a preference score. If an animal spends more time in a location predictive of exposure to a given drug than in a similar location not predictive of such exposure, then it is reasonable to assume that the drug has rewarding effects and is likely to serve as a positive reinforcer in a self-administration paradigm (Bardo & Bevins, 2000).

Moreover, if pretreatment with a given drug increases the preference score produced by another compound, it also seems reasonable to assume that the pretreatment drug increased the rewarding, or reinforcing, value of the other drug. As others have discussed, however, it is not easy to predict how pretreatment with that d tug will affect self-administration (Bardo & Bevins, 2000; Bozarth, 1987; Carr, Fibiger, & Phillips, 1989; Swerdlow, Gilbert, & Koob, 1989; Tzschentke, 1998; van der Kooy, 1987). Although response rate is a widely accepted index of behavior, "better", "more effective", or even "bigger" reinforcers are not necessarily associated with higher response rates under a given set of conditions (e.g., Pickens & Thompson, 1968; Poling, Lotfizadeh, & Edwards, 2017). As Poling et al. (2017) discuss, multiple response measures are necessary to adequately determine whether an antecedent manipulation, including daig pretreatment, alters the reinforcing effectiveness of another stimulus (e.g., drug). Given these considerations, it is clear that (a) the present results are not inconsistent with earlier findings regarding the interaction of cocaine and LVM in conditioned place preference assays (Tallarida et al., 2014, 2015) and (b) the present results do not provide a clear indication of whether or not LVM increased the reinforcing effectiveness of cocaine.

What the present results do indicate is simply that pretreatment with LVM at the two doses tested (1 and 10 mg/kg) never significantly increased cocaine self-administration. Instead, pretreatment with 10 mg/kg significantly reduced cocaine self-administration at the maintenance dose (0.56 mg/ kg/injection) and across a range of other doses (0.018-0.1 and 0.32-0.56 mg/kg/injection). As others have discussed at length (e.g., Balster & Lukas, 1985; Goldberg, Woods, & Schuster, 1971; Tallarida, 2000; Tallarida, Porreca, & Cowan, 1989), interpreting changes in drug-maintained responding induced by pretreatment with another compound poses conceptual challenges. These discussions make it clear that proper interpretation requires researchers to consider both the total number of responses emitted and moment-to-moment changes in responding within test sessions (Mello & Negus, 1996; Roberts, Loh, & Vickers, 1989). The present study examined both of these measures. LVM did not increase the total self-administered amount of cocaine, and it did not produce within-session patterns of responding characteristic of early satiation, which might be expected if the drug caused a given dose of cocaine (e.g., 0.56 mg/kg) to function as a much larger dose. Rather, regardless of whether or not LVM was administered, cocaine was administered in a temporal pattern similar to that observed by other researchers when similar doses were available (e.g., Pickens & Thompson, 1968). Therefore, the present data do not support the hypothesis that LVM is added to illicit cocaine to increase the amount of cocaine self-administered by street users in individual bouts of drug use.

To our knowledge, there are no published studies of the effects of LVM on schedule-controlled (e.g., FR) responding, and it is possible that LVM at the doses tested generally decreases operant behavior, regardless of reinforcer type. Such an action would be incompatible with LVM increasing cocaine self-administration under the conditions of the present study, and the effects of LVM on responding controlled by reinforcers other than cocaine are certainly worth investigating. Until such effects are known, a limitation of the present study is that its findings may be confounded by nonspecific effects of LVM. Another limitation is that LVM pretreatment was evaluated, but human users administer LVM simultaneously with cocaine, which might influence how the drugs interact. A third limitation is that only two doses of LVM--1 and 10 mg/kg--were examined, and it would be interesting to test intermediate doses.

Although the metabolic processes responsible for the breakdown of LVM are not entirely clear (Hess, Ritke, Broecker, Madea, & Musshoff, 2013), two of the predominant metabolites are pemoline and aminorex (Schedule IV and Schedule I stimulants, respectively). Pemoline and aminorex are reported to have amphetamine-like properties (Jamey, Kintz, & Raul, 2016; Woolverton, Massey, Winger, Patrick, & Harris, 1994); hence, adding LVM to cocaine may, over time, increase the intensity of the stimulant-like subjective effects produced by a single drug administration, as well as the duration of those effects. Hofmaier et al. (2014) proposed this hypothesis, citing work with cocaine and LVM that demonstrated coinhibition of both dopamine and norepinephrine transporters in HEK293 cells, with LVM responsible for substantially less potent inhibition than cocaine. Additionally, aminorex resulted in a substantial effect on dopamine, serotonin, and norepinephrine efflux and reuptake inhibition.

Given the clear role of mesolimbic dopamine in the reinforcing (Siciliano, Ferris, & Jones, 2015) and discriminative stimulus effects (Callahan, de La Garza, & Cunningham, 1997) of cocaine, such an action on dopamine transporters is likely to increase the reinforcing effectiveness of a given dose of cocaine. Such an action might well decrease the amount of cocaine administered by a lab animal or a human in a single setting. Indeed, pretreatment with cocaine (Briscoe et al., 1996) and other psychostimulants (Barrett, Miller, Dohrmann, & Caine, 2004; Mello & Newman, 2011) decreases subsequent cocaine self-administration and shifts the cocaine dose-effect curve leftward (Barrett et al., 2004; Mello & Newman, 2011), which is similar to the effects of LVM pretreatment in the present study.

Increases in mesolimbic dopamine resulting from the addition of LVM to cocaine could also increase the likelihood that bouts of self-administration will be repeated or could increase the perceived value (and worth) of the substance being administered. Either of these outcomes would be desirable from the perspective of a drug dealer, and further research using other procedures (e.g., drug discrimination, demand curve analysis, reinstatement) to examine them is certainly merited.

DOI 10.1007/s40732-017-0260-1

Acknowledgements The authors would like to thank Michael Berquist II for assistance with the statistical analysis.

Funding The research was conducted in partial fulfillment of the doctoral degree requirements for Zachary J. Zimmermann and was funded by MPI Research.

Compliance with Ethical Standards All experimental procedures and husbandry practices received prior approval from an institutional animal care and use committee and were conducted in full compliance with current national and international laws and in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011). Each of the authors contributed to the preparation of the manuscript.

Conflict of Interest The authors have no conflicts of interest to disclose.


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Zachary J. Zimmermann (1) * David V. Gauvin (1) * Alan Poling (2)

Published online: 16 October 2017

[mail] Zachary J. Zimmermann

(1) Neurobehavioral Sciences Department, MPI Research, Mattawan, MI 49071, USA

(2) Western Michigan University, Kalamazoo, MI 49008, USA

Caption: Fig. 1 Cocaine self-administration dose-effect function. The group mean number of injections administered in three consecutive daily 1-h unlimited-access test sessions is plotted as a function of the tested dose of cocaine (bars; M [+ or -] 1 SEM). The grand mean number of injections for each test sequence (3 days) is also shown as a line graph (solid lines). Each bar represents the mean number of injections earned during the test sessions. The data for saline (SAL) and 0.56 mg/kg/injection of cocaine (maintenance dose [MD]) are based on the performance of all rats (n = 32). All other data represent the performance of randomly selected subgroups of six rats. LVM = levamisole

Caption: Fig. 2 Representative samples of cumulative records generated for an unlimited-access 1 -h test session for the maintenance dose of cocaine (0.56 mg/kg/injection) for cocaine alone (top panel), 1 mg/kg of levamisole (LVM; middle panel), and 10 mg/kg of LVM (bottom panel)

Caption: Fig. 3 The mean (+ SEM) percentage of total cocaine self-administration responses emitted during the first quarter (i.e., 15 min) of each of the three consecutive 1-h sessions in which the per-injection dose of cocaine (COC) was 0.56 mg/kg and the rats were pretreated with the indicated dose of levamisole (LVM)
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Author:Zimmermann, Zachary J.; Gauvin, David V.; Poling, Alan
Publication:The Psychological Record
Article Type:Report
Date:Dec 1, 2017
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