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

Abstract

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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“…WIN55,212-2’s reinforcing effects were CB 1 receptor-mediated, as they were dose-dependently attenuated by SR141716A. As authors indicated, the lack of substitution with Δ 9 -THC seen in this study is problematic and may suggest that WIN55,212-2 self-administration may be of limited usefulness as a screening tool for detection of the reinforcing effects of potential cannabinoid medications (179). …”

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