Title

 

Authors

V. Micale^1,2, P.K. Nørregaard³ and C.T. Wotjak^1
1Max Planck Institute of Psychiatry, Research Group “Neuronal Plasticity”, Munich, Germany
²Dept. of Experimental and Clinical Pharmacology, University of Catania Medical School, Catania, Italy
³7TM Pharma, Hørsholm, Denmark

 

Abstract

Several studies have shown that activation or blockade of cannabinoid receptor type 1 (CB1) stimulates or inhibits food intake, respectively. Rimonabant was the first selective CB1 antagonist introduced into clinical practice for obesity treatment, but due to the notably increased rates of depression, anxiety, and suicidality it was withdrawn from the market (Le Foll et al., 2009). Preclinical studies including experiments in mutant mice with cell-type specific deletion of CB1 receptors suggest that anxiety-like behavior is mediated by central CB1 receptors, while food intake and metabolism are also highly affected by the peripheral CB1 receptors (Marsicano et al., 2002; Quarta et al., 2010). We have evaluated a novel peripherally restricted CB1 antagonist (TM38837) in terms of fear promoting consequences of systemic vs. intracerebral injections. TM38837 has been designed to have negligible CNS penetration while fully preserved peripheral actions. Male C57BL6/N mice underwent auditory-cued fear conditioning, followed by extinction training 1, 2, 3, and 10 days later that consisted of prolonged exposure to the auditory cue (180 s; Plendl and Wotjak, 2010). Different groups of mice were treated per os (p.o.) with TM38837(10, 30 or 100 mg/kg), rimonabant (= SR141716: 10 mg/kg; a brain penetrating CB1 antagonist which served as a positive control) or vehicle, 2 h prior the extinction training on d1, d2 and d3. TM38837 at the high dose (100 mg/kg) induced a significant increase of freezing behavior as compared to vehicle-treated group, similar to that induced by rimonabant (10 mg/kg) (p<0.001). At lower doses (10 and 30 mg/kg), however, TM38837 failed to induce any significant difference in the freezing response. To assess whether TM38837 would affect fear extinction if it could by-pass the blood brain barrier, we injected TM38837 (10 or 30 μg/mouse), rimonabant (1 μg/mouse) or vehicleintracerebroventricularly (i.c.v.) to new groups of conditioned mice 30 min. prior the extinction training. Both compounds (TM38837 and rimonabant) caused a sustained fear response to the tone, which was more pronounced after rimonabant treatment. TM38837 has been shown to be equipotent to rimonabant with regard to weight loss and effects on other metabolic parameters in rodent obesity models; hence these results are very encouraging for further development of TM38837 as a peripherally restricted CB1 receptor antagonist for indications such as obesity and metabolic disorders without inducing psychiatric side effects.

Le Foll et al. (2009) Psychopharmacology 205: 171-4
Marsicano et al. (2002) Nature 418: 530-4
Plendl and Wotjak (2010) J. Neurosci. 30: 4990-8.
Quarta et al. (2010) Cell. Metab. 11: 273-85.