Imaging Alterations in Endocannabinoid Metabolism in Schizophrenia

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DESCRIPTION (provided by applicant): While the role of dopamine in positive symptoms of schizophrenia (SCZ) is well established, it is increasingly recognized that cannabinoid signaling may also play a key role. Epidemiological studies have detected a twofold increase in the incidence of SCZ with early cannabis use, identifying it as a major trigger for the disease and thus providing the first link between cannabinoids and SCZ. The most studied of endocannabinoids (eCBs), anandamide (AEA), acts on the presynaptic CB1 receptors to modulate the release of neurotransmitters. Dramatic elevations of AEA were detected in cerebrospinal fluid of patients with SCZ in the midst of a psychotic episode, which normalize after psychosis resolution. Levels of AEA in the brain are tightly regulated through hydrolysis by the fatty acid amide hydrolase (FAAH) enzyme. FAAH therefore sets the tone of the eCB system. [11C]CURB, a carbon-11-labelled form of the potent irreversible FAAH inhibitor URB694, has recently been synthesized by our CAMH radiochemistry team and characterized for positron emission tomography (PET) imaging. The tracer exhibits high brain uptake, regional distribution that reflects known FAAH density, and excellent pharmacodynamic and pharmacokinetic properties, as established in animal studies. Furthermore, PET imaging in healthy volunteers (HV) was carried out to establish proof-of- concept, test-retest reproducibility and full body dosimetry, and to optimize kinetic modeling for [11C]CURB quantification. As the first radiotracer capable of assessing FAAH enzyme in-vivo, [11C]CURB goes beyond quantifying CB1 receptor expression by providing for the first time an index of AEA/FAAH in the living brain. We aim to measure FAAH in vivo by using [11C]CURB PET in antipsychotic-naive patients with SCZ. We hypothesize that [11C]CURB binding in the striatum and dorsolateral prefrontal cortex will be significantly lower in SCZ, as compared to HV. Additionally, we aim to explore the relation between regional FAAH levels and psychopathology and cognitive deficits in SCZ. Thirty-four participants (17 in SCZ and 17 in HV group) will undergo a 60 min [11C]CURB PET scan using a high-resolution research tomograph (HRRT). As previously established, the kinetics of [11C]CURB can be described with an irreversible two-tissue compartment model using metabolite-corrected [11C]CURB radioactivity in arterial plasma as input function, providing the reliable outcome measure ?k3. High resolution Magnetic Resonance Imaging (MRI) scans will provide an anatomical correlation needed to quantify regional tracer distribution in the PET image, as well as to measure regional cerebral blood flow. The proposed research will be the first exploration of changes in eCB signaling in a living brain evaluating for the first time AEA metabolism in SCZ. Our research is important since it may elucidate the neurochemical mechanism behind the role of cannabis in the onset of SCZ. This conceptual breakthrough would have significant impact on the field of psychosis, providing a new approach to treatment and prevention of SCZ.