Disorders of the Nervous System
Author: Andrés Pablo Varani | Email: andresvarani@gmail.com
Andrés P Varani1°, Martina Gomez Acosta1°, María C Fagnani1°, Gustavo Almeida Aguiar1°, Cecilia Tubert1°, Carlos A Pretell Annan1°, Juan E Belforte1°
1° Instituto de Fisiología y Biofísica Bernardo Houssay (Instituto Universidad de Buenos Aires – Consejo Nacional de Investigaciones Científicas y Técnicas). Paraguay 2155, 7°piso, (CP: 1121), Ciudad de Buenos Aires, Argentina.
Antidepressant fluoxetine (Flx) is clinically used to treat compulsive/perseverative behaviors in patients with obsessive-compulsive disorder and Tourette syndrome. Unveiling the pathophysiology of these disorders can aid in the rational design of therapeutic interventions. We aimed to study whether chronic Flx treatment reverses the compulsive/perseverative behaviors induced by chemogenetic inhibition of striatal cholinergic interneurons (SCIN). ChatCre heterozygous mice were injected with a viral vector (pAAV-hSyn-DIO-hM4DGi-mCherry) to selectively express inhibitory DREADD in SCIN. Mice were chronically treated with Flx (10 mg/kg, in drinking water) or water during 21 days after viral vector injection. Comprehensive behavioral tests were conducted using CNO or vehicle. The results showed that SCIN inhibition increased the grooming events, head dippings in the hole board test, frayed cotton for nest assembly and more buried marbles in water-treated mice. Long-term Flx treatment reversed the compulsive/perseverative behaviors induced by SCIN Inhibition. The expression and inhibitory effect of DREADDs in SCIN were confirmed through immunofluorescence and ex-vivo electrophysiology recordings. In summary, SCIN inhibition exacerbated ritualistic behaviors, suggesting that SCIN modulates these behaviors. Finally, the reversal caused by Flx validates the use of this drug to treat specific symptoms observed in these psychiatric disorders, lending support to our experimental model.