Translational research on the endocannabinoid system using postmortem brain tissue of mood disorder patients and an animal model of fear and stress

Posttraumatic stress disorder (PTSD) is an anxiety disorder that affects approximately 7% of the population. Individuals with PTSD experience significant functional impairments such as occupational and social dysfunction, as well as physical and mental health problems. A growing evidence suggests that the endocannabinoid system is involved in mood and anxiety disorders and may be an important drug target for the treatment of PTSD. Using gene expression microarrays and quantitative PCR, we investigated expression profiles of cannabinoid receptor genes (CNR1 and CNR2) in the prefrontal cortex (PFC) of humans and rodents. These subjects include a developmental cohort of normal individuals (n=46) ranging in age from birth to 49 years, a cohort of mood disorder patients (n=59) and unaffected age-matched controls (n=47), and mice selectively bred for high and low fear memory (n=26). Using a Pavlovian fear conditioning and extinction paradigm, we studied potential association between fear memory and cannabinoid receptor expression in multiple brain regions such as the PFC, caudate putamen, nucleus accumbens, amygdala, hippocampus and cerebellum of mice. The expression profiles of cannabinoid receptors were age-dependent and disease-specific. For example, CNR1, but not CNR2, levels were gradually decreased in the PFC of normal humans during postnatal development. In postmortem brains, CNR1 levels were increased in the subjects with major depression while decreased in the subjects with bipolar disorder as compared to the unaffected controls. Extinction of conditioned fear was associated with CNR1 expression levels in the PFC of mice. Increased CNR1 levels in the PFC of individuals with major depression and of mice with high fear suggest a common biological mechanism underlying stressful experience and depressive symptoms. Our translational approach combines data from the animal model of fear and stress, and from postmortem brains with mood disorders to enhance our understanding on the endocannabinoid system that may underlie these disorders.