Disruption of EphA/ephrin-a signaling in the nigrostriatal system reduces dopaminergic innervation and dissociates behavioral responses to amphetamine and cocaine.
We have investigated functional roles of EphA/ephrin-A signaling in the development and function of the nigrostriatal system by overexpressing a soluble, broad-range EphA receptor antagonist in the central nervous system of transgenic mice. Adult transgenic mice showed a 30-40% reduction in the total volume of the substantia nigra (SN) without detectable differences in the number of dopaminergic neurons. Using fluorogold retrograde tracing from the striatum, we detected a 40-50% reduction in the number of dopaminergic neurons that could be traced from this structure in transgenic mice, suggesting that, a lower proportion of these cells were able to reach the striatum after disruption of EphA/ephrin-A signaling. In spite of this, total dopamine content in the striatum of transgenic mice was comparable to wild type. Analysis of locomotor activity and its regulation by pharmacological treatments that stimulate dopaminergic transmission revealed an unexpected dissociation of the behavioral responses to amphetamine and cocaine. In particular, transgenic mice were relatively insensitive to amphetamine while retaining normal responsiveness to cocaine, which, to the best of our knowledge, represents the first report of a dissociation of the behavioral responses to these two psychostimulants. Together, these results reveal an unexpected role for EphA/ephrin-A signaling in the normal connectivity and function of midbrain dopaminergic neurons.
Sieber
Beth-Anne
BA
Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Kuzmin
Alexander
A
Canals
Josep M
JM
Danielsson
Anne
A
Paratcha
Gustavo
G
Arenas
Ernest
E
Alberch
Jordi
J
Ogren
Sven Ove
SO
Ibáñez
Carlos F
CF
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D036081:Receptors, Eph Family / Q000096:biosynthesis* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
D000661:Amphetamine; D036081:Receptors, Eph Family; D003042:Cocaine; D004298:Dopamine