Abstract
Antagonists of the muscarinic acetylcholine receptors (mAChRs) were among the first treatments for Parkinson's disease. However, the clinical utility of mAChR antagonists is limited by adverse effects associated with the blockade of multiple mAChR subtypes. Understanding the roles of specific mAChR subtypes in regulating basal ganglia and motor function could lead to the development of novel agents that have antiparkinsonian activity with fewer adverse effects. Using the novel, highly selective M1 antagonist N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide (VU0255035) and the M1 positive allosteric modulator benzylquinolone carboxylic acid, we investigated the roles of M1 receptors in cholinergic excitation and regulation of synaptic transmission in striatal medium spiny neurons (MSNs) and neurons in the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr). Electrophysiological studies demonstrate that M1 activation has excitatory effects on MSNs but plays little or no role in mAChR-mediated increases in firing frequency or the regulation of synaptic transmission in STN and SNr neurons. On the basis of this profile, M1-selective antagonists may have weak antiparkinsonian activity but would not have the full efficacy observed in nonselective mAChR antagonists. Consistent with this, the M1-selective antagonist VU0255035 partially reversed reserpine-induced akinesia and decreased haloperidol-induced catalepsy in rats but did not have the full efficacy observed with the nonselective mAChR antagonist scopolamine. These results suggest that the M1 receptor participates in the overall regulation of basal ganglia function and antiparkinsonian effects of mAChR antagonists but that other mAChR subtype(s) also play important roles at multiple levels of the basal ganglia motor circuit.
Footnotes
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants 1R01-NS065867, 5P50-NS071669] (to Z.X. and P.J.C., respectively); the National Institutes of Health National Institute of Mental Health [Grant 1U54-MH084659] (to C.W.L.); and the Dystonia Medical Research Foundation (to Z.X.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- PD
- Parkinson's disease
- ACh
- acetylcholine
- ACSF
- artificial cerebrospinal fluid
- BQCA
- benzylquinolone carboxylic acid
- CCh
- carbachol
- EPSC
- excitatory postsynaptic current
- IPSC
- inhibitory postsynaptic current
- Kir
- inwardly rectifying potassium channel
- KO
- knockout
- PPN
- pedunculopontine tegmental nucleus
- mAChR
- muscarinic acetylcholine receptor
- MSN
- medium spiny neuron
- PAM
- positive allosteric modulator
- SNr
- substantia nigra pars reticulata
- STN
- subthalamic nucleus
- VU0255035
- N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide.
- Received September 15, 2011.
- Accepted November 30, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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