Nigro-striatal dopamine activation lowers behavioral and neuronal phenotypes associated with obsessive-compulsive disorder

Casado-Sainz, A.; Gudmundsen, F.; Baerentzen, S. L.; Lange, D.; Ringsted, A.; Martinez-Tajada, I.; Medina, S.; Lee, H.; Svarer, C.; Keller, S. H.; Schain, M.; Kjaerby, C.; Fisher, P. M.; Cumming, P.; Palner, M.

doi:10.1101/2021.02.11.430770

bioRxiv · 10.1101/2021.02.11.430770

Nigro-striatal dopamine activation lowers behavioral and neuronal phenotypes associated with obsessive-compulsive disorder

Casado-Sainz, A.·Gudmundsen, F.·Baerentzen, S. L.·Lange, D.·Ringsted, A.·Martinez-Tajada, I.·Medina, S.·Lee, H.·Svarer, C.·Keller, S. H.·Schain, M.·Kjaerby, C.·Fisher, P. M.·Cumming, P.·Palner, M.

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Abstract

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervating the rat dorsal striatum. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement, as expected from dopamine release, rearings and time spend in center, while it also lowered self-grooming and increased prepulse inhibition in females. Remarkably, we observed reduced [18F]FDG metabolism in frontal cortex, following dopamine activation in the dorsal striatum, yet total glutamate levels-in this region were increased. A finding which may help explain the contradiction in some clinical studies of increased [18F]FDG metabolism and lower glutamate levels in diseases like OCD. Taken together, these results establish the importance of nigro-striatal dopamine transmission for modulating CSTC function, especially with respect to fronto-cortical activity, glutamate levels and behaviors related anxiety and compulsive actions. One Sentence SummaryDorsal striatum dopamine induce fronto-cortical hypoactivity and reduce compulsive behaviors in rats

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Casado-Sainz, A., Gudmundsen, F., Baerentzen, S. L., Lange, D., Ringsted, A., Martinez-Tajada, I., Medina, S., Lee, H., Svarer, C., Keller, S. H., Schain, M., Kjaerby, C., Fisher, P. M., Cumming, P., Palner, M.. 2021-02-11. Nigro-striatal dopamine activation lowers behavioral and neuronal phenotypes associated with obsessive-compulsive disorder. https://doi.org/10.1101/2021.02.11.430770

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