Effects of E-6776, a novel CB1 receptor antagonist, in rodent models of depression

Xavier Codony, Angels Fisas, Ana Montero, Manuel Laloya, Montserrat Jane, Helmut Buschmann, José Miguel Vela. Laboratorios Dr. Esteve, S.A., Barcelona, Spain.

Acute administration of cannabinoids may cause anxiogenic responses in humans. Δ9-THC, as well as endogenous cannabinoids and synthetic CB1 receptor agonists, have been widely reported to enhance anxiety-related behaviours in rodent models. However, the potent and selective CB1 receptor antagonist rimonabant has been found to display anxiolytic- or antidepressant-like effects, but also a lack of activity or even an anxiogenic-like profile (Akinshola et al., 1999; Haller et al., 2002; Griebel et al., 2005). Based on the above results, the antidepressant-like activity of the novel CB1 antagonist E-6776, (RS)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide, was evaluated.

Water Despair Test (WDT) in male CD-1 (25-30g, n= 59) and C57BL/6J mice (20-25g, n= 46) (Porsolt et al., 1977) and Tail Suspension Test (TST) in male CD-1 mice (25-30g, n= 80) (Steru et al., 1985), and WDT in male Sprague-Dawley rats (125-175g, n= 29) (Porsolt et al., 1978) were used. Administration was i.p., 30 min before test for mice and i.p. 1 h before test for rats. One Way Analysis of Variance was performed and Dunnett’s post-hoc multiple comparisons procedure or Dunn’s method were applied, where needed.

WDT in CD-1 mice. E-6776 produced a clear reduction in the immobility time at 3, 9 and 18 mg kg-1 (51.1±10.7s at 18 mg kg-1 vs. 130.9±13.2s for control group). WDT in C57BL/6J mice. E-6776 was not able to modify the immobility time at 9 mg kg-1 or 18 mg kg-1, but a clear reduction was found at 36 mg kg-1. TST in CD-1 mice. Although a clear tendency was shown, the differences in immobility time between groups administered with E-6776 and saline were not statistically significant. WDT in rats. E-6776 reduced the immobility time at 30 mg kg-1. No effect was seen at 10 mg kg-1.

WDT and TST evoke a characteristic behavioural immobility by exposing rodents to an inescapable situation. The immobility time can be reduced with a wide variety of antidepressant drugs, so they have been extensively used for measuring the behavioural effects of antidepressants and screening of new molecules. The effects of E-6776 in the WDT, both in mice and rats, and the tendency shown in TST, suggest that E-6776 exerts an antidepressant-like effect after acute administration.

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