title: Enhanced histamine H2 excitation of striatal cholinergic interneurons in L-DOPA-induced dyskinesia.
abstract: Levodopa is the most effective therapy for the motor deficits of Parkinson's disease (PD), but long term treatment leads to the development of L-DOPA-induced dyskinesia (LID). Our previous studies indicate enhanced excitability of striatal cholinergic interneurons (ChIs) in mice expressing LID and reduction of LID when ChIs are selectively ablated. Recent gene expression analysis indicates that stimulatory H2 histamine receptors are preferentially expressed on ChIs at high levels in the striatum, and we tested whether a change in H2 receptor function might contribute to the elevated excitability in LID. Using two different mouse models of PD (6-hydroxydopamine lesion and Pitx3(ak/ak) mutation), we chronically treated the animals with either vehicle or l-DOPA to induce dyskinesia. Electrophysiological recordings indicate that histamine H2 receptor-mediated excitation of striatal ChIs is enhanced in mice expressing LID. Additionally, H2 receptor blockade by systemic administration of famotidine decreases behavioral LID expression in dyskinetic animals. These findings suggest that ChIs undergo a pathological change in LID with respect to histaminergic neurotransmission. The hypercholinergic striatum associated with LID may be dampened by inhibition of H2 histaminergic neurotransmission. This study also provides a proof of principle of utilizing selective gene expression data for cell-type-specific modulation of neuronal activity.
authors: Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA.
authors: Sean Austin O
authors: SAO
authors: Lim
authors: Department of Neurology, University of Chicago, Chicago, IL 60637, USA.
authors: Rong
authors: R
authors: Xia
authors: Department of Neurology, University of Chicago, Chicago, IL 60637, USA; Department of Neurology, Columbia University, New York, NY 10032, USA.
authors: Yunmin
authors: Y
authors: Ding
authors: Department of Neurology, University of Chicago, Chicago, IL 60637, USA.
authors: Lisa
authors: L
authors: Won
authors: Envoy Therapeutics, Inc., Jupiter, FL 33458, USA.
authors: William J
authors: WJ
authors: Ray
authors: Envoy Therapeutics, Inc., Jupiter, FL 33458, USA.
authors: Stephen A
authors: SA
authors: Hitchcock
authors: Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA; Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL 60637, USA. Electronic address: dmcgehee@uchicago.edu.
authors: Daniel S
authors: DS
authors: McGehee
authors: Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA; Department of Neurology, University of Chicago, Chicago, IL 60637, USA; Department of Neurology, Columbia University, New York, NY 10032, USA. Electronic address: ujk2101@cumc.columbia.edu.
authors: Un Jung
authors: UJ
authors: Kang
mesh_terms: D000200:Action Potentials; D000818:Animals; D059329:Cholinergic Neurons / Q000378:metabolism / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology*; D004025:Dicyclomine / Q000008:administration & dosage; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology*; D015738:Famotidine / Q000008:administration & dosage; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007395:Interneurons / Q000378:metabolism / Q000502:physiology; D007980:Levodopa; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000150:complications*; D011970:Receptors, Histamine H2 / Q000378:metabolism*
chemical_list: D006635:Histamine H2 Antagonists; D011970:Receptors, Histamine H2; D007980:Levodopa; D004025:Dicyclomine; D015738:Famotidine
keywords: 6-OHDA lesion; Aphakia; Cholinergic interneuron; Famotidine; Histamine; Parkinson's disease; Striatum; l-DOPA induced dyskinesia