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.
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.
|Sanders, Teresa H (2017) Stimulation of Cortico-Subthalamic Projections Amplifies Resting Motor Circuit Activity and Leads to Increased Locomotion in Dopamine-Depleted Mice. Front Integr Neurosci 11:24|
|Chen, Erdong; Paré, Jean-Francois; Wichmann, Thomas et al. (2017) Sub-synaptic localization of Cav3.1 T-type calcium channels in the thalamus of normal and parkinsonian monkeys. Brain Struct Funct 222:735-748|
|Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland (2017) Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys. Neurobiol Dis 100:9-18|
|Dunn, Amy R; Stout, Kristen A; Ozawa, Minagi et al. (2017) Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proc Natl Acad Sci U S A 114:E2253-E2262|
|Huddleston, Daniel E; Langley, Jason; Sedlacik, Jan et al. (2017) In vivo detection of lateral-ventral tier nigral degeneration in Parkinson's disease. Hum Brain Mapp 38:2627-2634|
|Langley, Jason; Huddleston, Daniel E; Merritt, Michael et al. (2016) Diffusion tensor imaging of the substantia nigra in Parkinson's disease revisited. Hum Brain Mapp 37:2547-56|
|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|
|Wichmann, Thomas; DeLong, Mahlon R (2016) Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality? Neurotherapeutics 13:264-83|
|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|
|Galvan, Adriana; Devergnas, Annaelle; Pittard, Damien et al. (2016) Lack of Antiparkinsonian Effects of Systemic Injections of the Specific T-Type Calcium Channel Blocker ML218 in MPTP-Treated Monkeys. ACS Chem Neurosci 7:1543-1551|
Showing the most recent 10 out of 92 publications