title: MPP(+) -dependent inhibition of Ih reduces spontaneous activity and enhances EPSP summation in nigral dopamine neurons.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The effects of MPP(+) on SNc DA neurons in acute midbrain slices were investigated with electrophysiology techniques.
  
  
  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.
  
  
  CONCLUSIONS
  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: Department of Neurosciences, Psychology, Drug Research and Child Health - Section of Pharmacology and Toxicology, University of Florence, Florence, Italy. alessio.masi@unifi.it
authors: A
authors: A
authors: Masi
authors: R
authors: R
authors: Narducci
authors: E
authors: E
authors: Landucci
authors: F
authors: F
authors: Moroni
authors: G
authors: G
authors: Mannaioni
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D013045:Species Specificity; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D017448:Receptors, Dopamine D2; D000242:Cyclic AMP; D015655:1-Methyl-4-phenylpyridinium