Short communicationCannabinoid CB1 receptor is dispensable for memory extinction 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.).
References (22)
The effects of cannabinoids on the brain
Prog. Neurobiol.
(1999)- et al.
Behavioral mechanisms underlying inhibition of food-maintained responding by the cannabinoid receptor antagonist/inverse agonist SR141716A
Eur. J. Pharmacol.
(2004) - et al.
Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding
Pharmacol. Biochem. Behav.
(2000) SR 141716A enhances spatial memory as assessed in a radial-arm maze task in rats
Eur. J. Pharmacol.
(2000)- et al.
Endocannabinoids in cognition and dependence
Prostaglandins Leukot. Essent. Fat. Acids
(2002) - et al.
Behavioral and neural analysis of extinction
Neuron
(2002) - et al.
Effects of chronic delta(9)-tetrahydrocannabinol treatment on hippocampal extracellular acetylcholine concentration and alternation performance in the T-maze
Neuropharmacology
(2001) - et al.
Enhancement of memory in cannabinoid CB1 receptor knock-out mice
Eur. J. Pharmacol.
(1999) - et al.
Reduced attention in mice overproducing corticotropin-releasing hormone
Behav. Brain Res.
(2003) - et al.
SR141716A, a cannabinoid CB1 receptor antagonist, improves memory in a delayed radial maze task
Eur. J. Pharmacol.
(2003)
Cannabinoids and memory: animal studies
Curr. Drug Targets CNS Neurol. Disord.
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