Sunday, May 18, 2025
5/18/2025
Exploratory study of the cholinergic system in Obsessive Compulsive Disorder (OCD) - Obsessive-compulsive disorder (OCD) is a chronic, prevalent and disabling condition. The only medications that work as monotherapy for OCD are serotonin reuptake inhibitors. This reflects an incomplete understanding of the underlying cause(s) of the disorder and, accordingly, lack of mechanistically-defined targets for intervention. The goal of this application is to provide initial proof-of-concept for a novel target in OCD, based on exciting novel observations in a mouse model of OCD, the Sap90/PSD95-associated protein 3 (Sapap3) null mouse, now confirmed in a second genetic mouse model of OCD, the SLIT and NTRK-like protein-5 [Slitrk5] null mice. Our data in the Sapap3 mouse model, acquired by co-PI Joshua Plotkin, shows clear evidence for a link between the cholinergic system in the striatum and OCD-like symptoms as well as their treatment. In this mouse model we observe the following: 1) increased density of the cholinergic interneurons (CINs) in the striatum, 2) upregulation of the vesicular acetylcholine transporter (vAChT), 3) increase in ACh release in the striatum which corresponds to compulsive motor behavior. Furthermore, reducing striatal ACh release, by virally knocking down the vAChT within the dorsal striatum, mitigates the development of OCD-like symptoms. These novel data, showing abnormalities in the cholinergic system in the striatum of a valid mouse model of the disease that relate to emergence and treatment of OCD-like behavior, warrant a translational investigation of the cholinergic system in patients with OCD to probe for the possibility of cholinergic involvement in patients suffering from this devastating disease. Based on these observations we hypothesize that striatal ACh release capacity, as measured by vAChT density, is elevated in patients with OCD, and the magnitude of elevation relates to severity of OCD symptoms. We propose to scan 10 patients with OCD and 10 demographically matched controls with the newly developed vAChT Positron Emission Tomography (PET) tracer, [18F]VAT. This is a high-risk high reward novel investigation, based on robust preliminary data, that has the potential to identify the striatal cholinergic system as a novel target for therapeutic intervention in OCD. If successful, this proposal will inform the design of a larger study and provide POC for investigation of the cholinergic system in OCD. New therapies are urgently needed in OCD. Alternative or additional therapies to SRT drugs will improve the quality of life for patients suffering from this devastating disease.
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