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Research ArticleNeuropharmacology

Roles of the M1 Muscarinic Acetylcholine Receptor Subtype in the Regulation of Basal Ganglia Function and Implications for the Treatment of Parkinson's Disease

Zixiu Xiang, Analisa D. Thompson, Carrie K. Jones, Craig W. Lindsley and P. Jeffrey Conn
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 595-603; DOI: https://doi.org/10.1124/jpet.111.187856
Zixiu Xiang
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Analisa D. Thompson
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Carrie K. Jones
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Craig W. Lindsley
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P. Jeffrey Conn
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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.

    http://dx.doi.org/10.1124/jpet.111.187856.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleNeuropharmacology

M1 mAChR in Basal Ganglia

Zixiu Xiang, Analisa D. Thompson, Carrie K. Jones, Craig W. Lindsley and P. Jeffrey Conn
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 595-603; DOI: https://doi.org/10.1124/jpet.111.187856

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Research ArticleNeuropharmacology

M1 mAChR in Basal Ganglia

Zixiu Xiang, Analisa D. Thompson, Carrie K. Jones, Craig W. Lindsley and P. Jeffrey Conn
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 595-603; DOI: https://doi.org/10.1124/jpet.111.187856
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