Kirsten Bergmann(1), Oliver Ackaert(1), Eline van Maanen(1), Nelleke Snelder(1), Carla Maciag(2), Mike Quirk(2), Carin Wallsten(3), and Bart Ploeger(3)
(1)LAP&P Consultants BV, Leiden, The Netherlands; (2)CNSP iMed, AstraZeneca R&D, Wilmington, Delaware, USA; (3)Modelling & Simulation, CNSP iMed, AstraZeneca R&D, Södertälje, Sweden
Objectives: Prenatally stressed (PNS) rats show robust and long-lasting reduction in open-arm exploration on the elevated plus maze (EPM). The EPM is a plus-shaped maze with 2 open and 2 closed arms. An increase in exploration of the open arms by PNS rats indicates antidepressant effects. General activity is assessed by the number of entries into closed arms. The aim of the current study was to develop a count model to characterize the antidepressant and sedative effects of the two NMDA channel blockers, ketamine and AZD6765, on the number of open and closed entries in PNS rats.
Methods: Rats were dosed ip with saline, AZD6765 (0.3-10 mg/kg), or ketamine (1-10 mg/kg) and tested on the EPM at 1 h and 14 days postdosing. The vehicle group consisted of non-PNS and PNS rats. The rats were placed in the middle of the EPM and the number of open and closed entries was recorded for a 5 min period. Different Poisson models were investigated using NONMEM to describe the observed number of entries: normal and overdispersed Poisson with or without zero-inflation (to account for a higher probability of zero entries). Firstly, a model was developed to describe the sedative effect on the number of closed entries. Secondly, the sedative effect was included in the model to describe the number of open entries. Different dose-effect relationships were examined for the number of open and closed entries as well as the probability of zero entries. Final models were selected based on the objective function value and/or diagnostic plots (VPC and observed vs simulated distribution of the number of entries).
Results: An overdispersed Poisson model with zero-inflation adequately described the number of open and closed entries. A sigmoidal Emax dose-effect relationship was used to describe the sedative effect of ketamine. The antidepressant effect of both compounds could be described with an Emax model. The efficacy of AZD6765 was higher and the duration of the effect longer than for ketamine, even though the potency of ketamine was higher.
Conclusions: The NMDA channel blockers, ketamine and AZD6765, both showed antidepressant effects in the PNS-EPM model through prolonged increased explorative behavior compared with vehicle treatment. Using a count data modeling approach, a clear sedative effect of ketamine was quantified.
Reference: PAGE 21 (2012) Abstr 2431 [www.page-meeting.org/?abstract=2431]
Poster: CNS