Psychopharmacology (2004) 176: 223–232 DOI 10.1007/s00213-004-1877-8 ORIGINAL INVESTIGATION Carles Sanchis-Segura . Brandon H. Cline . Giovanni Marsicano . Beat Lutz . Rainer Spanagel Reduced sensitivity to reward in CB1 knockout mice Received: 17 December 2003 / Accepted: 10 March 2004 / Published online: 9 April 2004 # Springer-Verlag 2004 Abstract Rationale: Previous studies have demonstra- ted that the activation and blockade of the cannabinoid type 1 receptor (CB1) leads to an enhancement and decrease of the consumption of food and other orally ingested reinforcers, respectively. Objective: To gain further knowledge about the role of CB1 in sucrose/ saccharin reinforcing efficacy and intake, we tested CB1 knockout (CB1-KO) and littermate wild-type (WT) con- trol mice in several self-administration experimental protocols. Methods: Operant (fixed or progressive ratio schedule) and non-operant conditioning procedures were used. In addition, a choice analysis based on the “matching law” as well as a microstructural analysis of the intra-session pattern of self-administration was per- formed. Results: CB1-KO mice consume less sucrose under operant conditions or when using a two-bottle free choice procedure. Moreover, as revealed by additional behavioural analysis, CB1-KO mice exhibit a decreased sensitivity to the rewarding properties of sucrose. In agreement with this finding, the differences between WT and CB1-KO mice faded away when the palatability of sucrose was devaluated by adding quinine, but not when a non-caloric sweetener, saccharin, was available. Conclusions: These results demonstrate a modulatory role of CB1 in the determination of the rewarding properties of sucrose and probably, as suggested by previous studies, other reinforcers. Keywords Cannabinoid receptor 1 . Sucrose . Reinforcing efficacy . Reward . Matching law Introduction It has been shown that the activation of the endogenous cannabinoid system leads to an increase of ingestive behaviour in humans and in animal models. Thus, in addition to the well-known association between marijuana consumption and hyperphagia (reviewed in Cota et al. 2003a; Marsicano et al. 2003) several animal studies have established that the administration of exogenous (Koch 2001) or endogenous (Williams and Kirkham 1999) cannabinoids results in an enhanced food intake. More- over, these effects, as well as food intake in cannabinoid- naive animals, can be reduced by the administration of CB1 receptor antagonists (Arnone et al. 1997; Kirkham and Williams 2001). Taken together, it seems clear that the endogenous cannabinoid system, and more specifically the activation of CB1, are involved in the promotion of ingestive behaviours (reviewed in Cota et al. 2003a; Marsicano et al. 2003). However, the exact role of CB1 in the promotion of ingestive behaviours remains unclear. In fact, the hyper- phagic/anorectic actions of CB1 agonists/antagonists could result from changes in appetitive or consumatory processes or even both. Thus, CB1 agonists energize ingestive behaviour, advancing the onset of eating (Wil- liams and Kirkham 2002) and increasing the motivation of rats to obtain reinforcing fluids when their availability is limited by progressive ratio (PR) schedules (Gallate et al. 1999). These data suggest that CB1 activation can facilitate the appetitive processes of ingestive behaviour such as incentive motivation. Alternatively, CB1 activa- tion could be more related to consummatory processes such as palatability (orosensory rewarding properties). Thus, it has been proposed that CB1 antagonists produce a higher reduction in the ingestion of palatable foods or reinforcing fluids such as sucrose or alcoholic solutions (Arnone et al. 1997; Freedland et al. 2001; Perio et al. C. Sanchis-Segura . B. H. Cline . R. Spanagel (*) Department of Psychopharmacology, Central Institute for Mental Health, CIMH, University of Heidelberg, 68159 Mannheim, Germany e-mail: spanagel@zi-mannheim.de Tel.: +49-621-1703833 Fax: +49-621-1703837 C. Sanchis-Segura Area de Psicobiologia, Universitat Jaume I, Castello, Spain G. Marsicano . B. Lutz Molecular Genetics of Behaviour, Max Planck Institute of Psychiatry, Munich, Germany