title: Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons.
abstract: Typical antipsychotics can cause disabling side effects. Specifically, antagonism of D2R signaling by the typical antipsychotic haloperidol induces parkinsonism in humans and catalepsy in rodents. Striatal dopamine D2 receptors (D2R) are major regulators of motor activity through their signaling on striatal projection neurons and interneurons. We show that D2R signaling on cholinergic interneurons contributes to an in vitro pause in firing of these otherwise tonically active neurons and to the striatal dopamine/acetylcholine balance. The selective ablation of D2R from cholinergic neurons allows discrimination between the motor-reducing and cataleptic effects of antipsychotics. The cataleptic effect of antipsychotics is triggered by blockade of D2R on cholinergic interneurons and the consequent increase of acetylcholine signaling on striatal projection neurons. These studies illuminate the critical role of D2R-mediated signaling in regulating the activity of striatal cholinergic interneurons and the mechanisms of typical antipsychotic side effects.
authors.affiliation: Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Geetika
authors.initials: G
authors.lastname: Kharkwal
authors.affiliation: Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Brami-Cherrier
authors.affiliation: Departments of Neurology and Pharmacology, Columbia University, New York, NY 10032, USA.
authors.forename: José E
authors.initials: JE
authors.lastname: Lizardi-Ortiz
authors.affiliation: The Gladstone Institutes, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Alexandra B
authors.initials: AB
authors.lastname: Nelson
authors.affiliation: Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ramos
authors.affiliation: Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Del Barrio
authors.affiliation: Departments of Neurology and Pharmacology, Columbia University, New York, NY 10032, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.affiliation: The Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Anatol C
authors.initials: AC
authors.lastname: Kreitzer
authors.affiliation: Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: borrelli@uci.edu.
authors.forename: Emiliana
authors.initials: E
authors.lastname: Borrelli
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D018678:Cholinergic Agents / Q000494:pharmacology; D059329:Cholinergic Neurons / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects*; D008822:Mice, Transgenic; D017072:Neostriatum / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D018678:Cholinergic Agents; D017448:Receptors, Dopamine D2; D000109:Acetylcholine; D004298:Dopamine