Imaging dopamine transmission in comorbid schizophrenia and cannabis dependence

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DESCRIPTION (provided by applicant): Dopamine (DA) plays a role in the pathophysiology of schizophrenia and addiction. Imaging studies have shown consistently that dopamine is increased in striatal areas of the brain in schizophrenia, while it is blunted in addiction. Recently these observations received more topographical characterization from use of higher resolution scanners and better data analysis methods. These improvements have contributed to the following observations: DA transmission is predominantly blunted in the ventral striatum (VST) in addiction while, in schizophrenia, DA transmission is increased in the associative striatum, and, more specifically, in the precommissural caudate (preDCA). With this type of opposite dysregulation of DA transmission within the striatum, the intriguing next question is about dual diagnosis patients suffering from both schizophrenia and addiction, and in particular those suffering from cannabis dependence. Cannabis use is associated with higher risk for schizophrenia and more severe symptomatology. We propose that subjects with comorbid cannabis dependence and schizophrenia (DD for dual diagnosis) will display opposite alterations in DA transmission where the VST is blunted while the preDCA is increased. This would explain the drive to use drugs (low DA in VST) leading to psychotic symptoms (drugs may dysregulate DA in preDCA). Antipsychotics will exacerbate the hypodopaminergic tone in the VST leading to craving, drug use, non-adherence and a self-perpetuating vicious circle. We submitted a first RO1 to assess dopamine transmission in chronic cannabis dependence. Here we propose a small companion grant focused on dual diagnosis patients comorbid for cannabis dependence and schizophrenia. Twelve DD patients and 12 matched healthy controls (HC) will undergo PET imaging with [11C]raclopride and the D-amphetamine challenge. The main outcome measure will be the decrease in [11C]raclopride specific-to-nonspecific equilibrium partition coefficient (V3") due to amphetamine induced DA release, or V3". We expect that V3" will be increased in DD (n = 12) compared to HC (n = 12) in preDCA (SA2) and decreased in VST (SA1). This study is a first step towards a better understanding of the pathophysiology of DD, which may ultimately lead to better detection, prevention and treatment. Despite major improvements in our understanding of the pathophysiology of schizophrenia and addiction, very few studies have focused on the area of comorbidity between these two disorders. Substance abuse is clearly a widespread problem in schizophrenia and represents a challenging therapeutic and management problem. We propose a first small study to test a working model of dopamine dysregulation in the brains of patients with cannabis dependence and schizophrenia, which will lead to a better understanding of the pathophysiology of dual diagnosis and better detection, prevention and treatment.