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Anatomical Localization of Cav3.1 Calcium Channels and Electrophysiological Effects of T-type Calcium Channel Blockade in the Motor Thalamus of MPTP-treated Monkeys

Anatomical Localization of Cav3.1 Calcium Channels and Electrophysiological Effects of T-type Calcium Channel Blockade in the Motor Thalamus of MPTP-treated Monkeys

Annaelle Devergnas, Erdong Chen, Yuxian Ma, Ikuma Hamada, Damien Pittard, Stefan Kammermeier, Ariana P Mullin, Victor Faundez, Craig W Lindsley, Carrie Jones, Yoland Smith, Thomas Wichmann

J Neurophysiol. 2016 Jan 1;115(1):470-85.

PMID: 26538609

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1346233688	ML218		1346233-68-8	Price

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