The effects of rimonabant on hippocampal and cortical neurotrophic protein expression in rats reared in social isolation

Neda Assareh, Caitlin Jones, Charles A Marsden, David A Kendall, Kevin CF Fone

School of Biomedical sciences, University of Nottingham, Nottingham, Nottinghamshire, UK

Isolation rearing of rats after weaning is considered a neurodevelopmental model for producing, later in life, changes in behaviour and protein expression in some brains areas similar to those seen in schizophrenic patients (Review; Fone and Porkess et.al 2008). Endocannabinoids and their cognate receptors (predominantly cannabinoid CB1) have been implicated in schizophrenic pathology. The neurotrophin, BDNF, and its receptor TrkB and the mitogen-activated protein kinase ERK are suggested to play a role in the pathophysiology of mood and cognitive disorders (Coyle and Duman 2003). The aim of the present study was to determine the effects of the CB1 inverse agonist/antagonist rimonabant on expression of these proteins in the brains of isolation-reared rats.

Male Lister Hooded rats were housed either individually or in groups of 4 from post-natal day 28 for 6 weeks. After Isolation each group of isolated and socially reared rats received (ip) injections of either vehicle or rimonabant (2mg/kg or 5 mg/kg) on four occasions at one week intervals (weeks 7-10 post-isolation). The postmortem expression levels of BDNF, TrkB, ERK (42 and 44KD) and phospho-ERK (p-ERK) protein were measured using Western immunoblotting in the frontal cortex and hippocampus of isolated and social –housed rats treated with rimonabant compared with vehicle-treated controls. Statistical significance was assessed using unpaired t-tests.

There was a significant decrease in the p-ERK: ERK 42KD ratio in the frontal cortex of isolated compared with socially-reared rats (36.0 ±7.6%, p<0.05, n=7-8) which it was not changed in rimonabant-treated isolated compared with vehicle-treated isolated. The p-ERK:ERK ratio was also reduced in the hippocampus of isolated rimonabant versus isolated vehicle treated rats in both p-ERK:ERK 44KD (p<0.01, 58±6.3%, n=5) and p-ERK:ERK 42KD (0<001, 24±1.6%, n=5) although there was no difference between the vehicle-treated isolated versus vehicle-treated socially reared rats. There was a significant increase in TrkB levels in the frontal cortex of isolated rimonabant-treated compared to isolated vehicle-treated rats (p<0.01, 165±11.8%, n=5) but no alterations in vehicle-treated isolated, compared with socially reared rats in the frontal cortex or the hippocampus. There was no change in BDNF levels in frontal cortex or hippocampus of isolated versus socially reared rats or rimonabant-treated isolated versus rimonabant-treated socially reared rats. Rimonabant had no effects on BDNF, TrkB or the p-ERK; ERK 42 or 44 KD ratio in frontal cortex or hippocampus of socially reared rats.

In conclusion, in the isolation-reared rats, there was evidence of reduced basal ERK phosphorylation in the frontal cortex. Rimonabant in the isolation-reared rat caused a dramatic reduction in ERK phosphorylation in the hippocampus and significantly increased TrkB expression in the frontal cortex. The relevance of these changes in brain protein expression to schizophrenia-related behavioural adaptations induced by isolation rearing and manipulation of endocannabinoid signalling are the subject of additional studies.

Fone, K. C. & Porkness, M. V. (2008). Neurosci Biobehav Rev, 32, 1087-102.

Coyle, J. T. & Duman, R. S. (2003) Neuron, 38:157-160