Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys

J Neurophysiol. 2016 Jan 1;115(1):470-85. doi: 10.1152/jn.00858.2015. Epub 2015 Nov 4.


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.

Keywords: Parkinsonism; T-type calcium channel; nondopaminergic therapy; rebound burst.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Azabicyclo Compounds / administration & dosage*
  • Azabicyclo Compounds / pharmacology*
  • Basal Ganglia / metabolism
  • Basal Ganglia / ultrastructure
  • Benzamides / administration & dosage*
  • Benzamides / pharmacology*
  • Calcium Channel Blockers / administration & dosage*
  • Calcium Channels, T-Type / metabolism
  • Calcium Channels, T-Type / physiology*
  • Dendrites / metabolism
  • Dendrites / ultrastructure
  • Macaca mulatta
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Neural Pathways / ultrastructure
  • Neurons / drug effects*
  • Neurons / physiology*
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / physiopathology*
  • Thalamus / drug effects*
  • Thalamus / metabolism
  • Thalamus / physiology*
  • Thalamus / ultrastructure


  • Azabicyclo Compounds
  • Benzamides
  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • ML218 compound