FAAH inhibitor, URB-597, promotes extinction and CB 1 antagonist, SR141716, inhibits extinction of conditioned aversion produced by naloxone-precipitated morphine withdrawal, but not extinction of conditioned preference produced by morphine in rats Laurie A. Manwell a , Elham Satvat b , Stefan T. Lang a , Craig P. Allen a , Francesco Leri a , Linda A. Parker a, ⁎ a Department of Psychology, University of Guelph, Guelph, ON, Canada N1G 2W1 b Department of Psychology, Wilfrid Laurier University, Waterloo ONT abstract article info Article history: Received 31 May 2009 Received in revised form 31 July 2009 Accepted 6 August 2009 Available online 19 August 2009 Keywords: Conditioned preference Conditioned aversion CB 1 receptor Anandamide (AEA) Extinction learning Rat Converging evidence suggests that the endogenous cannabinoid (eCB) system is involved in extinction of learned behaviours. Using operant and classical conditioning procedures, the potential of the fatty acid amide (FAAH) inhibitor, URB-597, and the CB 1 antagonist/inverse agonist, SR141716, to promote and inhibit (respectively) extinction of learned responses previously motivated by either rewarding or aversive stimuli was investigated. In the operant conditioning procedure (Expt. 1), rats previously trained to lever press for sucrose reward were administered URB-597 (0.3 mg/kg) or the CB 1 antagonist/inverse agonist SR141716 (2.5 mg/kg) prior to each of three extinction trials. In the conditioned floor preference procedure (Expts 2a–d), rats trained to associate morphine with one of two distinctive floors were administered one of several doses of the CB 1 antagonist/inverse agonist, AM-251 (Expt 2a) or URB-597 (Expt 2b and 2d) prior to each extinction/ test trial wherein a choice of both floors was presented and prior to forced exposure to each floor (Expt 2c). In the conditioned floor aversion procedure (Expt. 3), rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered URB-597 or SR141716 prior to each of 24 extinction/testing trials. URB-597 did not promote and SR141716 did not reduce extinction rates for sucrose reward-induced operant responding (Expt. 1) or morphine-induced conditioned floor preference (Expts. 2a–d). In contrast, URB-597 facilitated, whereas SR141716 impaired, extinction of the conditioned floor aversion (Expt. 3). These data support previous reports that the eCB system selectively facilitates extinction of aversive memories. URB-597 may prove useful in targeting extinction of aversively motivated behaviours. © 2009 Elsevier Inc. All rights reserved. 1. Introduction Considerable evidence indicates that the endogenous cannabinoid (eCB) system is involved in extinction learning of aversively moti- vated learned behaviors (Marsicano et al., 2002; Varvel and Lichtman, 2002). Marsicano et al. (2002) reported that CB 1 knockout mice and wild-type mice administered the CB 1 inverse agonist/antagonist, SR141716 (Rimonabant), showed impaired extinction in classical auditory fear-conditioning tests, with unaffected memory acquisition and consolidation. Using the Morris water maze task, Varvel and Lichtman (2002) reported that CB 1 knockout mice and wild-type mice exhibited identical acquisition rates in learning to swim to a fixed platform; however, the CB 1 -deficient mice demonstrated consider- able deficits during a reversal task in which the location of the hidden platform was moved to the opposite side of the tank. Since animals deficient in CB 1 receptor activity show impairments in suppressing previously learned behaviors, cannabinoid agonists would be expected to facilitate extinction of learned behaviors in non-deficient animals. Indeed, Pamplona et al. (2006) recently reported that the potent cannabinoid receptor agonist WIN 55,212-2 facilitated extinc- tion of contextual fear memory and spatial memory in rats, whereas an ethyl derivative of SR141716 significantly impaired extinction. These results suggest that the eCB system modulates extinction of aversively motivated learned responses. With the recent discovery of drugs that enhance endogenous cannabinoids by blocking their reuptake (e.g., AM404) or by inhibiting the enzyme (fatty acid amide hydrolase [FAAH]) that deactivates anandamide (e.g., OL135 and URB-597), the effect of prolonging anandamide's activity during extinction learning has also been investigated (Chhatwal et al., 2005; Varvel et al., 2007). Chhatwal et al. (2005) reported that pretreatment with AM404 selectively facilitated extinction of fear potentiated startle in rats (Chhatwal et al., 2005), an effect that was reversed by SR141716 pretreatment. Varvel et al. (2007) reported that mice deficient in FAAH, either by genetic deletion (FAAH -/- ) or by pharmacological inhibition with OL135, Pharmacology, Biochemistry and Behavior 94 (2009) 154–162 ⁎ Corresponding author. Tel.: +1 519 824 4120, 56330; fax: +1 519 837 8629. E-mail address: parkerl@uoguelph.ca (L.A. Parker). 0091-3057/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2009.08.002 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh