DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor

Neuron. 2016 Jun 1;90(5):955-68. doi: 10.1016/j.neuron.2016.04.017. Epub 2016 May 5.


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.

MeSH terms

  • Animals
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Cyclic AMP / metabolism
  • Diterpenes / pharmacology
  • Diterpenes, Clerodane
  • Dopamine / metabolism
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / transplantation*
  • Dyskinesia, Drug-Induced / physiopathology*
  • Ethylamines / pharmacology
  • Female
  • Fetal Tissue Transplantation / adverse effects*
  • Gene Knock-In Techniques
  • Humans
  • Indoles / pharmacology
  • Oxidopamine
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / surgery
  • Postoperative Complications
  • Rats
  • Receptors, Serotonin / biosynthesis
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology*


  • 2-(5-chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine
  • Diterpenes
  • Diterpenes, Clerodane
  • Ethylamines
  • Indoles
  • Receptors, Serotonin
  • salvinorin B
  • serotonin 6 receptor
  • Oxidopamine
  • Cyclic AMP
  • Clozapine
  • clozapine N-oxide
  • Dopamine