Postnatal NMDA-inhibition induces alterations in CB1 receptor expression leading to schizophrenic-like behaviour in adulthood

Sharon Anavi-Goffer1, Shimon Rabichev2, Hodaya Dahan2, Ken Mackie3, Ruth A. Ross1, Ester Fride2. 1Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom, 2Ariel University Center, Ariel, Israel, 3The Linda and Jack Gill Center, Dept. Psychological and Brain Sciences, Indiana University, Bloomington, United States.

Schizophrenia affects 1% of the population and erupts mostly at late adolescence or early adulthood. This disease is associated with impairments of emotional and cognitive functions, which can be mimicked by phencyclidine (PCP), an NMDA receptor blocker. As the endocannabinoid system is intimately involved in brain wiring during CNS development, we hypothesised that early postnatal treatment of mice with PCP will induce changes in the endocannabinoid system and lead to “schizophrenia-like” behaviour.

The effects of administering PCP (20 mg/kg; subcutaneously) every other day between postnatal days 3 to 15 was evaluated with a variety of animal behaviour paradigms relevant to anxiety and symptoms associated with schizophrenia when animals had reached adulthood. We have also characterised the biochemical expression of CB1 receptors in different brain regions by Western blot analysis at the end of the treatment.

In the diencephalon/basal ganglia, CB1 receptor expression at 45 kDa was 63.16 ± 10.89% compared with vehicle 100 ± 12.2% (Student’s t-test p = 0.07; Vehicle 6/group; PCP 4/group; one litter). In the brain stem, CB1 receptor expression at 45 kDa was 67.95 ± 4.63% compared to saline controls 100 ± 5.64% Student’s t-test, p<0.002; Vehicle 8/group; PCP 6/group; two litters). At age 8 weeks, a significant increase in the acoustic startle reflex was observed in the treated animals compared to saline controls (Two-way ANOVA, p<0.0001 treatment, Df = 1,45 F = 26). Additionally, we observed a significant inhibition of the pre-pulse inhibition of the startle reflex (PPI) in the PCP-treated animals (Two-way ANOVA, p<0.03 treatment, Df = 1,40 F = 5.5). At age 12 weeks animals were tested in the ‘plus maze’ for ‘anxiety-like’ behaviour. The PCP-treated animals displayed increased anxiety measures in the plus maze test (ratio open/close, PCP 0.59 ± 0.12 vs. vehicle 1.08±0.15, p<0.05). Taken together, these results suggest that NMDA-induced alterations in the endocannabinoid system during postnatal development of the mouse brain contribute to the development of “schizophrenic-like” behaviour in adulthood.

SAG is supported by GW Pharmaceuticals and the National Institute for Psychobiology in Israel- founded by The Charles E. Smith Family, Young Investigator Award 244-09-2010.