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Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively-motivated learning task

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Abstract

The interaction of the cannabinoid CB1 receptor with its endogenous ligands plays an essential role in extinction of aversive memories (Marsicano, G., Wotjak, C.T., Azad, S.C., Bisogno, T., Rammes, G., Cascio, M.G., Hermann, H., Tang, J., Hofmann, C., Zieglgansberger, W., Di, M., V, Lutz, B., 2002. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534). The present study tested the generality of this observation in respect to positively-reinforced memories. To this end, male cannabinoid CB1 receptor deficient mice (CB1R−/−) and their wild-type littermate controls (CB1R+/+) were trained in an appetitively-motivated operant conditioning task, in which food-deprived animals received a food reward on nose-poking into an illuminated hole. During training, CB1R−/− turned out to be less motivated to participate in the task. After further restriction of daily food consumption, however, CB1R−/− reached the same level of performance as CB1R+/+ as far as number of correct responses and errors of omission are concerned. The accuracy of performance served as a measure for the memory of the light-reward association and was stable at similarly high levels over a retention period of 9 days without additional training (97.6±0.5% vs. 97.0±0.9% correct responses). During subsequent extinction training, the positive reinforcement was omitted. As a consequence, both CB1R−/− and CB1R+/+ showed a similar decline in accuracy of performance and total number of correct responses, accompanied by an increase in errors of omission. These data demonstrate that the cannabinoid CB1 receptor is not essential for extinction of the stimulus–response association in an appetitively-motivated learning task.

Introduction

Whereas pharmacological effects of cannabinoids on learning and memory have been well described (for reviews see Ameri, 1999, Lichtman et al., 2002, Sullivan, 2000, Castellano et al., 2003), the contribution of the endogenous cannabinoid system to these processes has remained enigmatic. Only recently, it has become evident that the role of endocannabinoids in cognition seems to predominantly relate to the retention of recognition memory (Reibaud et al., 1999, Terranova et al., 1996) and reference spatial memory (Lichtman, 2000, Wolff and Leander, 2003), with little consequences on working spatial memory (Hampson and Deadwyler, 2000, Ledent et al., 1999, Nava et al., 2001, Varvel and Lichtman, 2002). For instance, blockade of the cannabinoid CB1 receptor with a specific antagonist prolonged retention of juvenile recognition in adult mice and rats, restored juvenile recognition in aged mice and rats and disrupted the amnesic consequences of retroactive interference (Terranova et al., 1996). Accordingly, cannabinoid CB1 receptor deficient mice showed prolonged recognition of a familiar object as compared to wild-type littermate controls (Reibaud et al., 1999, Maccarrone et al., 2002).

Pharmacological blockade of the cannabinoid CB1 receptor improved memory performance in an appetitively-motivated spatial learning task, if a cannabinoid CB1 receptor antagonist was administered before or immediately after training (Lichtman, 2000, Wolff and Leander, 2003), suggesting a role of the endogenous cannabinoid system also in memory acquisition. The situation appeared to be different in aversively-motivated learning tasks. As assessed in cannabinoid CB1 receptor deficient mice, the cannabinoid CB1 receptor seems to be dispensable for both acquisition and consolidation of fear memories in a fear conditioning paradigm and spatial memory in a water maze (Marsicano et al., 2002, Varvel and Lichtman, 2002). In both tasks, the cannabinoid CB1 receptor seems to play a specific role in memory extinction (Marsicano et al., 2002, Varvel and Lichtman, 2002, Suzuki et al., 2004). So far, studies on molecular correlates of extinction have largely concentrated on aversive memories (for review see Myers and Davis, 2002). Little is known as to whether or not extinction of aversive and extinction of positive memories involve similar cellular and molecular processes. Therefore, the present study investigated memory extinction in an appetitively-motivated operant conditioning task in cannabinoid CB1 receptor deficient mice.

Section snippets

Animals

At an age of 11–14 weeks, adult male mice deficient for the cannabinoid CB1 receptor (CB1R−/−, n=10; Marsicano et al., 2002; F6 generation backcrossed to C57BL/6NCrl, Charles River, Bad Sulzfeld, Germany) and littermate controls (CB1R+/+, n=12) were housed individually in IVC-racks under standard laboratory conditions with food and water ad libitum and a 12 h:12 h light–dark cycle (lights on: 07:00 h). After 7 days of recording of ad libitum food consumption and body weights, mice were food

Results

As shown in Fig. 1A, CB1R−/− displayed more errors of omission than CB1R+/+ during acquisition phase A1 [Factor Genotype: F(1,20)=7.5, P=0.012; Genotype×Session interaction: F(11,220)=0.6, P=0.850], indicating that the mutants were less motivated to forage for food. Accordingly, a further reduction of the body weight in CB1R−/− during acquisition phase A2 equalized the performance of the two genotypes towards the end of training [Factor Genotype: F(1,20)=6.8, P=0.017; Genotype×Session

Discussion

The present study investigated the role of the cannabinoid CB1 receptor for memory extinction in an appetitively-motivated learning task. Reduction of the body weight to 85% sufficiently motivated CB1R+/+ controls, but not CB1R−/−, to participate in the task. To minimize potentially confounding influences of differences in motivation on extinction learning, the food supply was further reduced to 80% in CB1R−/−. Under these conditions, CB1R−/− and CB1R+/+ showed comparable levels of performance

Acknowledgements

We thank Kornelia Kamprath (MPI) for her comments on the manuscript. This work was supported by the NGFN, grant No. 01GR0103 and by Eumorphia, grant No. EU QLG2-CT-2002-00930 (W.W.) and by VW-Stiftung, grants No. I/78562 (C.T.W.) and I/78560 (B.L.) and a scholarship from the Hertie Foundation (B.L.).

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