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PhD à l'Institut Max-Planck de Munich (1997-2001)
Post-Doc, Institut Max-Planck, Munich (2001-2004)
CR1 Neurocentre Magendie, Bordeaux (2007)

111 publication(s) since Mars 2003:

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* equal contribution
The indicated IF have been collected by the Web of Sciences in

02/2006 | Endocr Rev   IF 15.2
The emerging role of the endocannabinoid system in endocrine regulation and energy balance
Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R

During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.

02/2006 | J Mol Med   IF 4.7
Vanilloid receptor (TRPV1)-deficient mice show increased susceptibility to dinitrobenzene sulfonic acid induced colitis
Massa F, Sibaev A, Marsicano G, Blaudzun H, Storr M, Lutz B

In the human colon, vanilloid receptor TRPV1 is overexpressed both in afferent nerve terminals and in epithelial cells during inflammation. In the past years, pharmacological experiments using TRPV1 agonists and antagonists revealed that TRPV1 receptors may play proinflammatory and protective roles in the gastrointestinal tract. Here, we applied a genetic approach to define the role of TRPV1 and analyzed the effects of dinitrobenzene sulfonic acid (DNBS)-induced colitis in TRPV1-deficient (TRPV1-/-) mice. Intrarectal infusion of DNBS induced increased inflammation in TRPV1-/- mice compared to wild-type littermates (TRPV1+/+) as evaluated by macroscopic scoring and myeloperoxidase assays. This finding indicates that TRPV1 receptors are required for the protection within sensory pathways that regulate the response following the initiation of colonic inflammation. Electrophysiological recordings from circular smooth-muscle cells, performed 8 and 24 h after DNBS treatment, revealed strong spontaneous oscillatory action potentials in TRPV1-/- but not in TRPV1+/+ colons, indicating an early TRPV1-mediated control of inflammation-induced irritation of smooth-muscle activities. These unexpected results suggest that TRPV1 receptors mediate endogenous protection against experimentally induced colonic inflammation.

2006 | J Endocrinol Invest   IF 3.4
Neuromodulatory functions of the endocannabinoid system
Marsicano G, Lutz B

The endocannabinoid system (ECS) has recently emerged as an important neuromodulatory system in the brain. Several neuronal functions are under the control of the cannabinoid receptor type 1 (CB1 receptor) and of its endogenous lipid ligands (endocannabinoids). CB1 receptors are widely expressed in the brain and their expression pattern reflects the complexity and the variety of functions of the ECS in neuronal activity. In particular, CB1 receptors are present at different levels in several brain regions and in distinct neuronal subpopulations. Endocannabinoids were described to act as retrograde transmitters at synaptic level in many brain regions. Interestingly, the mechanisms governing endocannabinoid-controlled synaptic modulation can vary depending on the region and the neuronal circuit. At physiological and pathophysiological level, the ECS has recently been shown to play important regulatory roles in several brain processes, including the modulation of memory processing and the control of excessive neuronal activity. The discovery of the ECS represents a hallmark in neuroscience research, and the exploitation of its numerous physiological and pathophysiological functions is a promising avenue for therapeutic applications.

10/2005 | Faseb J   IF 5.4
The endocannabinoid system drives neural progenitor proliferation.
Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z, Guzman M, Galve-Roperh I

The discovery of multipotent neural progenitor (NP) cells has provided strong support for the existence of neurogenesis in the adult brain. However, the signals controlling NP proliferation remain elusive. Endocannabinoids, the endogenous counterparts of marijuana-derived cannabinoids, act as neuromodulators via presynaptic CB1 receptors and also control neural cell death and survival. Here we show that progenitor cells express a functional endocannabinoid system that actively regulates cell proliferation both in vitro and in vivo. Specifically, NPs produce endocannabinoids and express the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase (FAAH). CB1 receptor activation promotes cell proliferation and neurosphere generation, an action that is abrogated in CB1-deficient NPs. Accordingly, proliferation of hippocampal NPs is increased in FAAH-deficient mice. Our results demonstrate that endocannabinoids constitute a new group of signaling cues that regulate NP proliferation and thus open novel therapeutic avenues for manipulation of NP cell fate in the adult brain.

09/2005 | Gastroenterology   IF 19.2
Fatty acid amide hydrolase controls mouse intestinal motility in vivo
Capasso R, Matias I, Lutz B, Borrelli F, Capasso F, Marsicano G, Mascolo N, Petrosino S, Monory K, Valenti M, Di Marzo V, Izzo A A

BACKGROUND & AIMS: Fatty acid amide hydrolase (FAAH) catalyzes the hydrolysis both of the endocannabinoids (which are known to inhibit intestinal motility) and other bioactive amides (palmitoylethanolamide, oleamide, and oleoylethanolamide), which might affect intestinal motility. The physiologic role of FAAH in the gut is largely unexplored. In the present study, we evaluated the possible role of FAAH in regulating intestinal motility in mice in vivo. METHODS: Motility was measured by evaluating the distribution of a fluorescent marker along the small intestine; FAAH messenger RNA (mRNA) levels were analyzed by reverse-transcription polymerase chain reaction (RT-PCR); endocannabinoid levels were measured by isotope-dilution, liquid chromatography, mass spectrometry. RESULTS: Motility was inhibited by N-arachidonoylserotonin (AA-5-HT) and palmitoylisopropylamide, 2 selective FAAH inhibitors, as well as by the FAAH substrates palmitoylethanolamide, oleamide, and oleoylethanolamide. The effect of AA-5-HT was reduced by the CB1 receptor antagonist rimonabant and by CB1 deficiency in mice but not by the vanilloid receptor antagonist 5'-iodoresiniferatoxin. In FAAH-deficient mice, pharmacologic blockade of FAAH did not affect intestinal motility. FAAH mRNA was detected in different regions of the intestinal tract. CONCLUSIONS: We conclude that FAAH is a physiologic regulator of intestinal motility and a potential target for the development of drugs capable of reducing intestinal motility.

07/03/2005 | Eur J Pharmacol   IF 3.2
Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively-motivated learning task
Holter S M, Kallnik M, Wurst W, Marsicano G, Lutz B, Wotjak C T

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.

03/11/2004 | J Neurosci   IF 6.1
Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling.
Azad SC, Monory K, Marsicano G, Cravatt BF, Lutz B, Zieglgansberger W, Rammes G

Endocannabinoids are crucial for the extinction of aversive memories, a process that considerably involves the amygdala. Here, we show that low-frequency stimulation of afferents in the lateral amygdala with 100 pulses at 1 Hz releases endocannabinoids postsynaptically from neurons of the basolateral amygdala of mice in vitro and thereby induces a long-term depression of inhibitory GABAergic synaptic transmission (LTDi) via a presynaptic mechanism. Lowering inhibitory synaptic transmission significantly increases the amplitude of excitatory synaptic currents in principal neurons of the central nucleus, which is the main output site of the amygdala. LTDi involves a selective mGluR1 (metabotropic glutamate receptor 1)-mediated calcium-independent mechanism and the activation of the adenylyl cyclase-protein kinase A pathway. LTDi is abolished by the cannabinoid type 1 (CB1) receptor antagonist SR141716A and cannot be evoked in CB1 receptor-deficient animals. LTDi is significantly enhanced in mice lacking the anandamide-degrading enzyme fatty acid amide hydrolase. The present findings show for the first time that mGluR activation induces a retrograde endocannabinoid signaling via activation of the adenylyl cyclase-protein kinase A pathway and the release of anandamide. Furthermore, the results indicate that anandamide decreases the activity of inhibitory interneurons in the amygdala. This disinhibition increases the activity of common output neurons and could provide a prerequisite for extinction by formation of new memory.

11/04/2004 | J Clin Invest   IF 12.3
The endogenous cannabinoid system protects against colonic inflammation.
Massa F*, Marsicano G*, et al.


09/2003 | Gastroenterology   IF 19.2
An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice.
Izzo AA , Capasso F , Costagliola A , Bisogno T , Marsicano G , Ligresti A , Matias I , Capasso R , Pinto L , Borrelli F , Cecio A , Lutz B , Mascolo N , Di Marzo V

BACKGROUND & AIMS: Cholera toxin (CT) is the most recognizable enterotoxin causing secretory diarrhea, a major cause of infant morbidity and mortality throughout the world. In this study, we investigated the role of the endogenous cannabinoid system (i.e., the cannabinoid receptors and their endogenous ligands) in CT-induced fluid accumulation in the mouse small intestine. METHODS: Fluid accumulation was evaluated by enteropooling; endocannabinoid levels were measured by isotope-dilution gas chromatography mass spectrometry; CB(1) receptors were localized by immunohistochemistry and their messenger RNA (mRNA) levels were quantified by reverse-transcription polymerase chain reaction (PCR). RESULTS: Oral administration of CT to mice resulted in an increase in fluid accumulation in the small intestine and in increased levels of the endogenous cannabinoid, anandamide, and increased expression of the cannabinoid CB(1) receptor mRNA. The cannabinoid receptor agonist CP55,940 and the selective cannabinoid CB(1) receptor agonist arachidonoyl-chloro-ethanolamide inhibited CT-induced fluid accumulation, and this effect was counteracted by the CB(1) receptor antagonist SR141716A, but not by the CB(2) receptor antagonist SR144528. SR141716A, per se, but not the vanilloid VR1 receptor antagonist capsazepine, enhanced fluid accumulation induced by CT, whereas the selective inhibitor of anandamide cellular uptake, VDM11, prevented CT-induced fluid accumulation. CONCLUSIONS: These results indicate that CT, along with enhanced intestinal secretion, causes overstimulation of endocannabinoid signaling with an antisecretory role in the small intestine.

08/2003 | J Clin Invest   IF 12.3
The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.
Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U

The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.