Gene expression signature in brain regions exposed to long-term psychosocial stress following acute challenge with cannabinoid drugs

Abstract

Repeated exposure to life stressors can overwhelm the body's capacity to restore homeostasis and result in severe negative consequences. Cannabinoid CB 1 receptors are highly expressed in the Central Nervous System (CNS) and regulate both glucocorticoid signalling and neurotransmitter release. In rodents, WIN55212.2 is a full agonist at the cannabinoid receptor type-1, while Rimonabant is a potent and selective cannabinoid inverse agonist at this receptor. This study aims to investigate the effect of long-term psychosocial stress following acute challenge with cannabinoid drugs on gene expression in distinct brain regions; this is done by employing digital multiplexed gene expression analysis. We found that repeated stress increased cortical mRNA levels of dopamine receptor D2, while the expression of neuregulin-1 decreased in both the prefrontal cortex and cerebellum. Further, we found that the acute injection of the agonist WIN55212.2 reduced striatal levels of dopamine receptor D2, while the use of inverse agonist Rimonabant acted in the opposite direction. The analysis of the interaction between the drugs and repeated stress revealed that defeat mice treated with WIN55212.2 showed lower expression of a set of myelin-related genes, as did the expression of SRY-box 10 and dopamine receptors-D1 and -D2 in the prefrontal cortex when compared to vehicle. In addition, in the hippocampus of stressed mice treated with WIN55212.2, we found an elevated expression of oligodendrocyte transcription factor-1, -2 and zinc finger protein 488 when compared to vehicle. In comparison to vehicle, an increase in 2′,3′-Cyclic nucleotide 3′-phosphodiesterase and oligodendrocyte transcription factor-1 occurred in the cerebellum of stressed animals treated with the agonist. Moreover, treatment with Rimonabant under the influence of stress induced an overexpression of a set of myelin-related genes in the prefrontal cortex when compared to WIN-treated animals. In conclusion, repeated stress interfered with the dopaminergic system in the prefrontal cortex. We demonstrated that the expression of dopamine receptor D2 in the striatum was mediated by the CB 1 receptor. Stressed mice exposed to either WIN55212.2 or Rimonabant displayed pronounced deficits in CNS myelination. In addition, the pharmacological blockage of CB 1 receptor in stressed mice deregulated the expression of dopamine receptors and might lead to dysfunctions in dopamine metabolism.