Prediction and Prevention of Prescription Drug Abuse: Role of Preclinical Assessment of Substance Abuse Liability

Marusich, Julie A.; Lefever, Timothy W.; Novak, Scott P.; Blough, Bruce E.; Wiley, Jenny L.

doi:10.3768/rtipress.2013.op.0014.1307

Cited by 13 publications

(8 citation statements)

References 44 publications

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“…self-administration of WIN55,212-2, an aminoalkylindole cannabinoid, was acquired and maintained over the course of this study. Substitution of other doses of WIN55,212-2 produced an inverted U-shaped dose-effect function which resembled that obtained with cocaine in rats trained to self-administer this stimulant (e.g., see Marusich et al, 2013). Rimonabant dose-dependently attenuated the number of infusions of the 0.01 mg/kg/infusion WIN55,212-2 training dose, suggesting CB 1 receptor mediation of WIN55,212-2’s reinforcing effects.…”

Section: 0 Discussionsupporting

confidence: 57%

“…Hence, self-administration was not as robust as for other classes of self-administered drugs such as stimulants (e.g., see Marusich et al, 2013). Nevertheless, when other WIN55,212-2 doses were substituted, orderly dose-effect functions were obtained, with a descending limb evident in the first determination and a full inverted U-shaped function observed in the second determination.…”

Section: 0 Discussionmentioning

confidence: 99%

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Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model

Lefever¹,

Marusich²,

Antonazzo³

et al. 2014

Pharmacology Biochemistry and Behavior

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Because Δ 9 -tetrahydrocannabinol (THC) has been a false negative in rat intravenous selfadministration procedures, evaluation of the abuse potential of candidate cannabinoid medications has proved difficult. One lab group has successfully trained self-administration of the aminoalkylindole WIN55,212-2 in rats; however, their results have not been independently replicated. The purpose of this study was to extend their model by using a within-subjects design, with the goal of establishing a robust method suitable for substitution testing of other cannabinoids. Male Long-Evans rats were trained to self-administer WIN55,212-2 (0.01 mg/kg/ infusion) on a fixed ratio 3 schedule. Dose-effect curves for WIN55,212-2 were determined, followed by vehicle substitution and a dose-effect curve with THC. WIN55,212-2 selfadministration was acquired; however, substitution with THC did not maintain responding above vehicle levels. Dose-dependent attenuation by rimonabant confirmed CB 1 receptor mediation of WIN55,212-2's reinforcing effects. Vehicle substitution resulted in a session-dependent decrease in responding (i.e., extinction). While this study provides systematic replication of previous studies, lack of substitution with THC is problematic and suggests that WIN55,212-2 selfadministration may be of limited usefulness as a screening tool for detection of the reinforcing effects of potential cannabinoid medications. Clarification of underlying factors responsible for failure of THC to maintain self-administration in cannabinoid-trained rats is needed. Keywords abuse liability; aminoalkylindole; cannabinoids; methods; rats; reinforcing effects; selfadministration; Δ 9 -tetrahydrocannabinol; WIN55,212-2 IntroductionSelf-administration, an animal model of the reinforcing effects of drugs, has high predictive validity for drugs that are abused by humans for their euphoric effects (Ator and Griffiths, 1987;Johanson and Balster, 1978). Consequently, intravenous (i.v.) self-administration has become the "gold standard" in preclinical assessment of abuse liability and is a primary method recommended by the U.S. Food and Drug Administration for use in screening novel compounds (Food and Drug Administration, 2010). However, not all drugs abused by © 2013 Elsevier Inc. All rights reserved.To whom correspondence should be addressed: Jenny L. Wiley, Ph.D., RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA, Phone: (1) 919-541-7276, Fax: (1) 919-541-6499, jwiley@rti.org. Conflicts of interest:There are no conflicts of interest.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to th...

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Section: 0 Discussionsupporting

confidence: 57%

Section: 0 Discussionmentioning

confidence: 99%

Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model

Lefever¹,

Marusich²,

Antonazzo³

et al. 2014

Pharmacology Biochemistry and Behavior

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“…The purpose of the present study was to determine whether females and males develop differential tolerance to the antinociceptive effects of a cannabinoid. Characterizing drug tolerance is important not only as it relates to a drug’s abuse/dependence potential (Marusich et al, 2013), but also, in the case of analgesics, to their ability to continue to relieve pain with repeated use.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

Wakley

Wiley

Craft

2014

Drug and Alcohol Dependence

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Background Sex differences in cannabinoid effects have been reported in rodents, with adult females typically being more sensitive than adult males. The present study compared the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) in adult, gonadally intact female vs. male rats. Methods Cumulative dose-effect curves were obtained for THC (1.0–18 mg/kg i.p.) on warm water tail withdrawal and paw pressure tests. Vehicle or the sex-specific ED80 dose for THC was administered twice daily for 9 days; THC dose-effect curves were then re-determined. Results On the pre-chronic test day, THC was significantly more potent in females than males in producing antinociception on the tail withdrawal and paw pressure tests. After 9 days of twice-daily THC treatment (5.4 mg/kg/injection in females, 7.6 mg/kg/injection in males), THC potency on both tests decreased more in females than males. On the tail withdrawal test, chronic THC produced 4.2- vs. 2.8-fold increases in ED50 values in females vs. males, respectively. On the paw pressure test, chronic THC produced 4.4- vs. 2.9-fold increases in ED50 values in females vs. males, respectively. Chronic THC treatment did not significantly disrupt estrous cycling in females. Conclusions These results demonstrate that – even when sex differences in acute THC potency are controlled for – females develop more antinociceptive tolerance to THC than males. Given the importance of drug tolerance in the development of drug dependence, these results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure.

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“…Compounds with alkyl group (butyl to hexyl) substitution for the morpholinoethyl group of WIN55,212-2 also dose-dependently substituted in CP55,940-trained rats at potencies consistent with their CB 1 affinity, whereas the heptyl compound did not substitute, nor did it bind to CB 1 receptors (Wiley, et al, 1998). Later studies showed that indole-derived cannabinoids JWH-018, JWH-073, AM-2233, and AM-5983 also substituted for Δ 9 -THC in rats and/or rhesus monkeys (Brents, et al, 2013; Ginsburg, et al, 2012; Järbe, et al, 2010; Järbe, et al, 2011; Marusich, et al, 2013), with rimonabant reversal suggesting CB 1 mediation of their Δ 9 -THC-like effects (Ginsburg, et al, 2012; Järbe, et al, 2011). In Δ 9 -THC-trained mice, two phenylacetylindoles (JWH-204 and JWH-205) and two tetramethylcyclopropyl ketone indoles (UR-144 and XLR-11) with high affinity (K i < 30 nM) for the CB 1 receptor substituted, whereas another phenylacetylindole (JWH-202) with low affinity (K i > 1500 nM) did not (Vann, et al, 2009; Wiley, et al, 2013).…”

Section: 0 Introductionmentioning

confidence: 99%

Cross-substitution of Δ9-tetrahydrocannabinol and JWH-018 in drug discrimination in rats

Wiley

Lefever

Cortes

et al. 2014

Pharmacology Biochemistry and Behavior

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Synthetic indole-derived cannabinoids, originally developed to probe cannabinoid CB1 and CB2 receptors, have become widely abused for their marijuana-like intoxicating properties. The present study examined the effects of indole-derived cannabinoids in rats trained to discriminate Δ9-tetrahydrocannabinol (Δ9-THC) from vehicle. In addition, the effects of Δ9-THC in rats trained to discriminate JWH-018 from vehicle were assessed. Adult male Sprague-Dawley rats were trained to discriminate 3 mg/kg Δ9-THC or 0.3 mg/kg JWH-018 from vehicle. JWH-018, JWH-073, and JWH-210 fully substituted in Δ9-THC-trained rats and Δ9-THC substituted in JWH-018-trained rats. In contrast, JWH-320, an indole-derived cannabinoid without affinity for CB1 receptors, failed to substitute for Δ9-THC. Pre-treatment with 1 mg/kg rimonabant significantly reduced responding on the JWH-018-associated lever in JWH-018-trained rats. These results support the conclusion that the interoceptive effects of Δ9-THC and synthetic indole-derived cannabinoids show a large degree of overlap, which is predictive of their use for their marijuana-like intoxicating properties. Characterization of the extent of pharmacological differences among structural classes of cannabinoids, and determination of their mechanisms remain important goals.

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Prediction and Prevention of Prescription Drug Abuse: Role of Preclinical Assessment of Substance Abuse Liability

Cited by 13 publications

References 44 publications

Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model

Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model

Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

Cross-substitution of Δ9-tetrahydrocannabinol and JWH-018 in drug discrimination in rats

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