| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
4 Nicotinic Receptors: Substantia Nigra Dopaminergic Neurons are Hypersensitive to Agonist and Lost Postnatally
1 Department of Neurology, University of Leipzig, Leipzig, Saxonia, Germany
2 Division of Biology, California Institute of Technology, Pasadena, California, USA
3 Department of Neurology, University of Leipzig, Leipzig, Saxonia, Germany; Division of Biology, California Institute of Technology, Pasadena, California, USA
* To whom correspondence should be addressed. E-mail: johannes{at}caltech.edu.
This study analyzes the electrophysiological cause and behavioral consequence of dopaminergic cell loss in a knock-in mouse strain bearing hypersensitive nicotinic 
4 receptor subunits ("L9'S mice"). Adult brains of L9'S mice show moderate loss of substantia nigra dopaminergic neurons and of striatal dopaminergic innervation. Amphetamine-stimulated locomotion is impaired, reflecting a reduction of dopamine stored in presynaptic vesicles. Recordings from dopaminergic neurons in L9'S mice show that 10 µM nicotine depolarizes cells and increases spiking rates in L9'S cells, but hyperpolarizes and decreases spiking rates in wild-type (WT) cells. Thus dopaminergic neurons of L9'S mice have an excitatory response to nicotine which is qualitatively different from that of WT neurons. The cause of dopaminergic cell death is therefore probably an increased sensitivity to acetylcholine or choline of 4-containing nicotinic receptors. Hypersensitive excitatory stimulation during activation of 4-containing receptors provides the first evidence for cholinergic excitotoxicity as a cause of dopaminergic neuron death. This novel concept may be relevant to the pathophysiology of Parkinson's disease.
This article has been cited by other articles:
|
|
 |
|
  M. Fedi, S. F. Berkovic, I. E. Scheffer, G. O'Keefe, C. Marini, R. Mulligan, S. Gong, H. Tochon-Danguy, and D. C. Reutens Reduced striatal D1 receptor binding in autosomal dominant nocturnal frontal lobe epilepsy Neurology, September 9, 2008; 71(11): 795 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Damaj, C. Fonck, M. J. Marks, P. Deshpande, C. Labarca, H. A. Lester, A. C. Collins, and B. R. Martin Genetic Approaches Identify Differential Roles for {alpha}4beta2* Nicotinic Receptors in Acute Models of Antinociception in Mice J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1161 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Milosevic, M. Maisel, F. Wegner, J. Leuchtenberger, R. H. Wenger, M. Gerlach, A. Storch, and J. Schwarz Lack of Hypoxia-Inducible Factor-1{alpha} Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling J. Neurosci., January 10, 2007; 27(2): 412 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Schwarz, S. C. Schwarz, O. Dorigo, A. Stutzer, F. Wegner, C. Labarca, P. Deshpande, J. S. Gil, A. J. Berk, and H. A. Lester Enhanced expression of hypersensitive {alpha}4* nAChR in adult mice increases the loss of midbrain dopaminergic neurons FASEB J, May 1, 2006; 20(7): 935 - 946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fonck, B. N. Cohen, R. Nashmi, P. Whiteaker, D. A. Wagenaar, N. Rodrigues-Pinguet, P. Deshpande, S. McKinney, S. Kwoh, J. Munoz, et al. Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive {alpha}4* Nicotinic Receptors J. Neurosci., December 7, 2005; 25(49): 11396 - 11411. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
