Document Detail

MPP(+) -dependent inhibition of I(h) reduces spontaneous activity and enhances EPSP summation in nigral dopamine neurons.
MedLine Citation:
PMID:  23323755     Owner:  NLM     Status:  Publisher    
BACKGROUND AND PURPOSE: 1-methyl-4-phenylpyridinium (MPP(+) ), a potent parkinsonizing agent in primates and rodents, is a blocker of mitochondrial complex I, therefore MPP(+) -induced parkinsonism is believed to depend largely on mitochondrial impairment. However, it has recently been proposed that other mechanisms may participate in MPP(+) -induced toxicity. We tackled this issue by probing the effects of an acute application of MPP(+) on substantia nigra pars compacta (SNc) dopamine (DA) neurons. EXPERIMENTAL APPROACH: The effects of MPP(+) on SNc DA neurons in acute midbrain slices were investigated with electrophysiology techniques. KEY RESULTS: MPP(+) (50 μM) was able to (1) hyperpolarize SNc DA neurons by ∼ 6 mV, (2) cause an abrupt and marked (over 50%) reduction of the spontaneous activity and (3) inhibit the hyperpolarization-activated inward current (I(h) ). MPP(+) shifted I(h) activation curve towards negative potentials by ∼11 mV both in Wistar rats and C57/BL6 mice. Inhibition was voltage- and concentration-dependent (I(max) = 47%, IC(50) = 7.74 μM). MPP(+) slowed I(h) activation kinetics at all potentials. These effects were not dependent on (i) block of mitochondrial complex I/fall of ATP levels, (ii) activation of type 2 dopamine receptor and (iii) alteration of cAMP metabolism. Finally, MPP(+) -dependent inhibition of I(h) facilitated temporal summation of eEPSPs in SNc DA, but not in CA1 hippocampal neurons. CONCLUSIONS AND IMPLICATIONS: Reduced functionality of I(h) in SNc DA neurons, via increased responsiveness towards synaptic excitation, might play a role in MPP(+) -induced parkinsonism and, possibly, in the pathogenesis of human Parkinson's.
A Masi; R Narducci; E Landucci; F Moroni; G Mannaioni
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-17
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G. Pieraccini 6, 50139, Firenze, Italy.
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