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Several studies into cannabinoid receptor type 1 expression in the brains of schizophrenic patients had revealed confusing results. The authors of this paper had previously demonstrated that in the dorsolateral prefrontal cortex, CB1R expression was significantly lower than in healthy controls. Other studies had reported either the same levels of CB1R expression as healthy individuals or higher levels of expression.
In order to shed some light on this mystery, the authors conducted a series of experiments to ascertain whether CB1R expression is lower in a slightly different area of the dorsolateral prefrontal cortex in the same subjects and a new cohort; whether the same expression is seen in patients with major depressive disorder (MDD); and whether other external factors like cannabis use could be the cause.
Although there were relatively few patients studied, the results were striking: the immunoreactivity of the brains of schizophrenics in these areas was significantly lower than in healthy brains and brains with MDD. Furthermore, the authors found that this difference was not attributable to other factors.
This study reinforced the view that in the brains of schizophrenic patients, the crucial signaling system of the endocannabinoid system is impaired. The higher rates of schizophrenia amongst cannabis users had indicated that this might be the case, but it was a long time before there was clinical evidence as to why this might be the case.
CB1 receptors are both inhibitory and excitatory proteins; depending on where they are and their context, they can have very different effects. This makes them both very important and hard to study. However, the authors have theorized that one of the proteins, GABA, that is controlled in some way by CB1Rs, is very important in the pathology of schizophrenia. In the brains that were studied, low levels of CB1Rs were found in areas known to be associated with schizophrenia.
When lower than normal CB1R expression is found, the whole signaling chain can get dysregulated. GABA signaling is different in the brains of schizophrenics.
Although it is too early to make definitive statements, this study points to the likelihood of a signaling system involving CB1R and GABA that is not passing signals in the way that it would in a normal brain. This impairs the signals and communication between parts of the brain and the very processing of information that is essential for a clear mind.
The areas of the brain studied in this study are very small but important. Knowing that the ECS is dysregulated here is very useful for building a model of why schizophrenia happens and what could potentially be done about it. However, there is a substantial amount of work to be done before even a vaguely representative model of a schizophrenic brain can be built.
Another limitation of potential therapy is that by administering cannabinoids to correct the dysregulation in that specific part of the brain, other parts of the brain that use endocannabinoid signaling would be disrupted without very specific targeting, something that is currently impossible.
The brains of schizophrenics are significantly different in terms of their endocannabinoid system in certain parts of the brain.ECS differences in schizophrenia