MPP(+) -dependent inhibition of Ih reduces spontaneous activity and enhances EPSP summation in nigral dopamine neurons.
Br J Pharmacol
; 169(1): 130-42, 2013 May.
Article
em En
| MEDLINE
| ID: mdl-23323755
ABSTRACT
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. EXPERIMENTALAPPROACH:
The effects of MPP(+) on SNc DA neurons in acute midbrain slices were investigated with electrophysiology techniques. KEYRESULTS:
MPP(+) (50 µM) was able to (i) hyperpolarize SNc DA neurons by â¼6 mV; (ii) cause an abrupt and marked (over 50%) reduction of the spontaneous activity; and (iii) inhibit the hyperpolarization-activated inward current (Ih ). MPP(+) shifted Ih activation curve towards negative potentials by â¼11 mV both in Wistar rats and in C57/BL6 mice. Inhibition was voltage- and concentration-dependent (Imax = 47%, IC50 = 7.74 µM). MPP(+) slowed Ih 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 DA receptor; and (iii) alteration of cAMP metabolism. Finally, MPP(+) -dependent inhibition of Ih facilitated temporal summation of evoked EPSPs in SNc DA, but not in CA1 hippocampal neurons. CONCLUSION AND IMPLICATIONS Reduced functionality of Ih 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Substância Negra
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1-Metil-4-fenilpiridínio
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Potenciais Pós-Sinápticos Excitadores
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Neurônios Dopaminérgicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article