Abstract Rationale: Endogenous and exogenous canna- binoids acting through the CB1 cannabinoid receptors are implicated in the control of a variety of behavioural and neuroendocrine functions, including emotional re- sponses, and learning and memory processes. Recently, knockout mice deficient in the CB1 cannabinoid receptor have been generated, and these animals result in an ex- cellent tool to evaluate the neurophysiology of the en- dogenous cannabinoid system. Objectives: To establish the role of the CB1 cannabinoid receptor in several emo- tional-related behavioural responses, including aggres- siveness, anxiety, depression and learning models, using CB1 knockout mice. Methods: We evaluated the sponta- neous responses of CB1 knockout mice and wild-type controls under different behavioural paradigms, includ- ing the light/dark box, the chronic unpredictable mild stress, the resident–intruder test and the active avoidance paradigm. Results: Our findings showed that CB1 knock- out mice presented an increase in the aggressive re- sponse measured in the resident–intruder test and an an- xiogenic-like response in the light/dark box. Further- more, a higher sensitivity to exhibit depressive-like re- sponses in the chronic unpredictable mild stress proce- dure was observed in CB1 knockout mice, suggesting an increased susceptibility to develop an anhedonic state in these animals. Finally, CB1 knockout mice showed a sig- nificant increase in the conditioned responses produced in the active avoidance model, suggesting an improve- ment of learning and memory processes. Conclusions: Taken together these findings demonstrate that endoge- nous cannabinoids through the activation of CB1 recep- tors are implicated in the control of emotional behaviour and participate in the physiological processes of learning and memory. Keywords Cannabinoid · CB1 receptor · Chronic unpredictable mild stress · Resident-intruder test · Active avoidance · Depression-like state Introduction The endocannabinoid system is involved in controlling several behavioural responses in the central nervous system (CNS), such as locomotor activity (Dewey 1986), nociception (Lichtman and Martin 1991a, 1991b; Calignano et al. 1998; Ledent et al. 1999), learning and memory (Ferrari et al. 1999; Reibaud et al. 1999; Böhme et al. 2000), as well as in the physiopathological process- es leading to drug abuse (Tanda et al. 1997, 2000; Martin et al. 2000; Valjent and Maldonado, 2000). However, the implication of this endogenous system in regulating emotional responses is poorly understood. Physiological actions of endocannabinoids in the CNS are mediated by the activation of a specific cannabinoid receptor, the CB1 receptor (Matsuda et al. 1990). This receptor is widely distributed in the CNS (Herkenham et al. 1991; Tsou et al. 1997), being present in the limbic system and in the brain areas related to stress responses, such as the central amygdala and the paraventricular nucleus of the hypothalamus. In addition, endocannabinoids could acti- vate the hypothalamic–pituitary–adrenal (HPA) axis (Weidenfel et al. 1994), the neuroendocrine system in- volved in the responses to emotional stress. Both the neuroanatomical localisation of the CB1 cannabinoid re- ceptor and its physiological implication in the control of HPA axis support the idea that this receptor participates in regulating emotional responses (Devane et al. 1988, 1992). However, previous studies have reported unclear and contradictory results concerning on the role of CB1 cannabinoid receptors in anxiety. In line with this, the acute administration of canna- binoids may cause anxiogenic responses in humans M. Martin · R. Maldonado · O. Valverde ( ✉ ) Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, C/ Doctor Aiguader 80, 08003 Barcelona, Spain e-mail: olga.valverde@cexs.upf.es Tel.: +34-93-5422830, Fax: +34-93-5422802 C. Ledent · M. Parmentier IRIBHN, Université libre de Bruxelles, 1070 Brussels, Belgium Psychopharmacology (2002) 159:379–387 DOI 10.1007/s00213-001-0946-5 ORIGINAL INVESTIGATION Miquel Martin · Catherine Ledent · Marc Parmentier Rafael Maldonado · Olga Valverde Involvement of CB1 cannabinoid receptors in emotional behaviour Received: 18 March 2001 / Accepted: 30 September 2001 / Published online: 20 November 2001 © Springer-Verlag 2001