Effects of E-6776, a novel cb1 receptor antagonist, in novel object discrimination and prepulse inhibition in rats

Xavier Codony1, Helge Slotten2, Helmut Buschmann1, José Miguel Vela1, Kevin Fone2. 1Laboratories Dr. Esteve, S.A., Barcelona, Spain, 2Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom.

The cannabinoid system has been noted to be involved in cognitive processes (Wolff & Leander, 2003; Takahashi et al., 2005). Marijuana intake in humans induces cognitive impairment. In rodents, cannabinoid agonists induce deficits in working memory and attentional function (Lichtman & Martin, 1996; Malone et al., 2004). To determine the activity of E-6776, (RS)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide, a novel CB1 receptor antagonist, on cognition in rats, Novel Object Discrimination (NOD) and PrePulse Inhibition (PPI) tests were used for memory and attention evaluation, respectively.

Male Lister-hooded rats (265-375g, n= 12) were used for NOD experiments following a previously reported methodology (King et al., 2003). Male Sprague-Dawley rats (225-300g, n= 46) were used for PPI experiments, under standard procedures (Geyer et al., 2001). In NOD experiments, one-way repeated measures analysis of variance (ANOVA) was used to study the effect of treatment on discrimination ratio, and post hoc comparisons using Bonferroni’s Multiple Comparison Test, where appropriate. In the PPI experiments, ANOVA was performed and Dunnett’s post-hoc multiple comparisons procedure applied or Dunn’s method, when needed.

NOD: The control group was unable to discriminate the novel object after a 4 h inter-trial interval, with Recognition Index (RI) slightly above the chance level (50%). Recognition of the novel object was enhanced by E-6776 at 3 and 10 mg kg-1, with RI around 65% (p<0.01) for both doses. PPI: The CB1 receptor antagonist E-6776 did not affect startle response when given alone (9 mg kg-1, i.p.). Increasing intensities of the prepulse (3dB, 6dB, 12dB) induced prepulse inhibition of the startle response up to 54.5 ± 4.3% at 12dB intensity. As expected, this effect was disrupted by apomorphine (-14.1% at 0.1 mg kg-1, and 2.9% at 0.2 mg kg-1, for the 12dB prepulse intensity). E-6776 (9 mg kg-1) was not able to reverse the apomorphine effect.

NOD: The results obtained are in agreement with the proposed involvement of the CB1 receptor in the regulation of memory. PPI: The failure of E-6776 to reverse the apomorphine-induced disruption of PPI suggests low antipsychotic potential.

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