MPP(+) -dependent inhibition of Ih reduces spontaneous activity and enhances EPSP summation in nigral dopamine neurons.

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.

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 (i) hyperpolarize SNc DA neurons by ∼6 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 ∼11 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.

• Authors: A Masi, R Narducci, E Landucci, F Moroni, G Mannaioni
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 169 Issue 1 Pg. 130-42 (May 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23323755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

Chemical References

• Receptors, Dopamine D2
• Cyclic AMP
• 1-Methyl-4-phenylpyridinium

Topics

• 1-Methyl-4-phenylpyridinium (administration & dosage, toxicity)
• Animals
• Cyclic AMP (metabolism)
• Dopaminergic Neurons (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Electrophysiological Phenomena
• Excitatory Postsynaptic Potentials (drug effects)
• Hippocampus (drug effects, metabolism)
• Inhibitory Concentration 50
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria (metabolism)
• Rats
• Rats, Wistar
• Receptors, Dopamine D2 (drug effects, metabolism)
• Species Specificity
• Substantia Nigra (drug effects, metabolism)
• Synapses (drug effects, metabolism)