Intra-putaminal muscarinic receptor agonist infusion induces a dystonic phenotype in non-human primates

Dystonia is a debilitating motor disorder of unclear pathophysiology, for which no specific pharmacological treatment is available in most cases. So far, several genetic models of dystonia suggesting a potential dysregulation of the intrastriatal cholinergic system have been obtained in rodents. However, in most cases, these animals did not exhibit a clear phenotype of dystonia but less specific motor impairments. In this study, we engineered an original model of dystonia in non-human primates by increasing cholinergic tone in the sensorimotor striatum. Chronic infusion of oxotremorine, a non-selective muscarinic agonist, into the putamen of non-human primates led to abnormal postures and dystonic movements, supported by EMG recordings. These motor abnormalities were associated with striatal hypermetabolism and significant changes in the firing rate of external and internal pallidum neurons. Furthermore, the pattern of neuronal activity in the internal pallidum was disrupted, and low-frequency oscillatory activity emerged in local field potentials within this structure. These data directly demonstrate, for the first time, in non-human primates that putaminal cholinergic dysregulation plays a crucial role in the pathophysiology of dystonia by disrupting both striatopallidal pathways.