title: Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys.
abstract: Conventional anti-Parkinsonian dopamine replacement therapy is often complicated by side effects that limit the use of these medications. There is a continuing need to develop nondopaminergic approaches to treat Parkinsonism. One such approach is to use medications that normalize dopamine depletion-related firing abnormalities in the basal ganglia-thalamocortical circuitry. In this study, we assessed the potential of a specific T-type calcium channel blocker (ML218) to eliminate pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in Parkinsonian monkeys. We also carried out an anatomical study, demonstrating that the immunoreactivity for T-type calcium channels is strongly expressed in the motor thalamus in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. At the electron microscopic level, dendrites accounted for >90% of all tissue elements that were immunoreactive for voltage-gated calcium channel, type 3.2-containing T-type calcium channels in normal and Parkinsonian monkeys. Subsequent in vivo electrophysiologic studies in awake MPTP-treated Parkinsonian monkeys demonstrated that intrathalamic microinjections of ML218 (0.5 μl of a 2.5-mM solution, injected at 0.1-0.2 μl/min) partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts. The drug also attenuated oscillatory activity in the 3-13-Hz frequency range and increased gamma frequency oscillations. However, ML218 did not normalize Parkinsonism-related changes in firing rates and oscillatory activity in the beta frequency range. Whereas the described changes are promising, a more complete assessment of the cellular and behavioral effects of ML218 (or similar drugs) is needed for a full appraisal of their anti-Parkinsonian potential.
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia; Udall Center of Excellence for Parkinson's Disease Research at Emory University, Atlanta, Georgia; adeverg@emory.edu.
authors.forename: Annaelle
authors.initials: A
authors.lastname: Devergnas
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia; Udall Center of Excellence for Parkinson's Disease Research at Emory University, Atlanta, Georgia;
authors.forename: Erdong
authors.initials: E
authors.lastname: Chen
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia; Udall Center of Excellence for Parkinson's Disease Research at Emory University, Atlanta, Georgia;
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia; Udall Center of Excellence for Parkinson's Disease Research at Emory University, Atlanta, Georgia;
authors.forename: Ikuma
authors.initials: I
authors.lastname: Hamada
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia; Udall Center of Excellence for Parkinson's Disease Research at Emory University, Atlanta, Georgia;
authors.forename: Damien
authors.initials: D
authors.lastname: Pittard
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia; Udall Center of Excellence for Parkinson's Disease Research at Emory University, Atlanta, Georgia; Klinikum der Universität München, Neurologische Klinik und Poliklinik, München, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Kammermeier
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, Georgia;
authors.forename: Ariana P
authors.initials: AP
authors.lastname: Mullin
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, Georgia; Center for Social Translational Neuroscience, Emory University, Atlanta, Georgia;
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
authors.affiliation: Department of Pharmacology and Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology and Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Carrie
authors.initials: C
authors.lastname: Jones
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia; Udall Center of Excellence for Parkinson's Disease Research at Emory University, Atlanta, Georgia; Department of Neurology, School of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia; Udall Center of Excellence for Parkinson's Disease Research at Emory University, Atlanta, Georgia; Department of Neurology, School of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wichmann
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage* / Q000494:pharmacology*; D001479:Basal Ganglia / Q000378:metabolism / Q000648:ultrastructure; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D020747:Calcium Channels, T-Type / Q000378:metabolism / Q000502:physiology*; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D008253:Macaca mulatta; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000503:physiopathology*; D013788:Thalamus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure
chemical_list: D053961:Azabicyclo Compounds; D001549:Benzamides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; C000611565:ML218 compound
keywords: Parkinsonism; T-type calcium channel; nondopaminergic therapy; rebound burst