Antagonists at muscarinic acetylcholine receptors (mAChRs) are commonly used in parkinsonian patients as an alternative to dopaminergic replacement therapies. The mAChR antagonists are very effective for treating symptoms, but their clinical utility is often limited by significant central and peripheral side effects. It is likely that the adverse effects of mAChR antagonists are due to the fact that available compounds are nonselective and have similar antagonist potencies at all of the five mAChR subtypes (termed Ml - M5). Development of an understanding of the individual mAChR subtypes involved in modulating basal ganglia function could provide a basis for development of mAChR antagonists that selectively block individual mAChR subtypes and may have antiparkinsonian efficacy with reduced adverse effect liability compared with the non-selective mAChR antagonists. We have made a major breakthrough in developing the first highly selective allosteric modulators of M1, M4, and M5 mAChR subtypes. In preliminary studies, we found that Ml, M4 and M5 mAChRs regulate neuronal excitability and inhibitory synaptic transmission in key nuclei of the basal ganglia. Specifically, the available data suggest to us that blockade of Ml and/or M4 mAChRs could have antiparkinsonian effects through reduction of pathologically increased and abnormally patterned neuronal activity in the subthalamic nucleus or the substantia nigra pars reticulata, while M5 activation may be beneficial, as M5 receptors appear to depolarize neurons in the substantia nigra pars compacta which may increase striatal dopamine levels. In the proposed studies, we plan to test these hypotheses by a thorough analysis of the electrophysiologic effects of our novel subtype-specific mAChR active compounds, and through in-vivo testing of these agents in acute and chronic rodent models of Parkinson's disease. Parallel immunohistochemcal studies (Core B) will examine the synaptic and subcellular distribution of the mAChR subtypes in the subthalamic nucleus and substantia nigra. These experiments are highly significant, as they may identify new classes of antiparkinsonian agents that promise effective treatment of parkinsonian patients with fewer side effects than currently possible.

Public Health Relevance

The proposed studies evaluate the utility of subtype-selective muscarinic receptor antagonists to normalize basal ganglia activity in parkinsonian animals in vitro, and to have antiparkinsonian effects in vivo. If successful, these studies may identify a group of highly effective antiparkinsonian drugs with fewer side effects that currently available treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS071669-04
Application #
8539098
Study Section
Special Emphasis Panel (ZNS1-SRB-E)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$291,405
Indirect Cost
$68,381
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Chen, Erdong; Paré, Jean-Francois; Wichmann, Thomas et al. (2016) Sub-synaptic localization of Cav3.1 T-type calcium channels in the thalamus of normal and parkinsonian monkeys. Brain Struct Funct :
Wichmann, Thomas; DeLong, Mahlon R (2016) Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality? Neurotherapeutics 13:264-83
Yung, Cheryl; Sha, Di; Li, Lian et al. (2016) Parkin Protects Against Misfolded SOD1 Toxicity by Promoting Its Aggresome Formation and Autophagic Clearance. Mol Neurobiol 53:6270-6287
Alter, Shawn P; Stout, Kristen A; Lohr, Kelly M et al. (2016) Reduced vesicular monoamine transport disrupts serotonin signaling but does not cause serotonergic degeneration. Exp Neurol 275 Pt 1:17-24
Bowman, F DuBois; Drake, Daniel F; Huddleston, Daniel E (2016) Multimodal Imaging Signatures of Parkinson's Disease. Front Neurosci 10:131
Galvan, Adriana; Hu, Xing; Smith, Yoland et al. (2016) Effects of Optogenetic Activation of Corticothalamic Terminals in the Motor Thalamus of Awake Monkeys. J Neurosci 36:3519-30
Sampat, Radhika; Young, Sarah; Rosen, Ami et al. (2016) Potential mechanisms for low uric acid in Parkinson disease. J Neural Transm (Vienna) 123:365-70
Sanders, Teresa H; Jaeger, Dieter (2016) Optogenetic stimulation of cortico-subthalamic projections is sufficient to ameliorate bradykinesia in 6-ohda lesioned mice. Neurobiol Dis 95:225-37
Devergnas, Annaelle; Chen, Erdong; Ma, Yuxian et al. (2016) 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 115:470-85
Iskhakova, Liliya; Smith, Yoland (2016) mGluR4-containing corticostriatal terminals: synaptic interactions with direct and indirect pathway neurons in mice. Brain Struct Funct 221:4589-4599

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