st-1936 and Parkinsonian-Disorders

Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.

Topics: Animals; Clozapine; Cyclic AMP; Diterpenes; Diterpenes, Clerodane; Dopamine; Dopaminergic Neurons; Dyskinesia, Drug-Induced; Ethylamines; Female; Fetal Tissue Transplantation; Gene Knock-In Techniques; Humans; Indoles; Oxidopamine; Parkinsonian Disorders; Postoperative Complications; Rats; Receptors, Serotonin