Function of dopamine transporter is compromised in DYT1 transgenic animal model in vivo
Article first published online: 2 FEB 2010
© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry
Journal of Neurochemistry
Volume 113, Issue 1, pages 228–235, April 2010
How to Cite
Hewett, J., Johansen, P., Sharma, N., Standaert, D. and Balcioglu, A. (2010), Function of dopamine transporter is compromised in DYT1 transgenic animal model in vivo. Journal of Neurochemistry, 113: 228–235. doi: 10.1111/j.1471-4159.2010.06590.x
- Issue published online: 3 MAR 2010
- Article first published online: 2 FEB 2010
- Received October 12, 2009; revised manuscript received January 7, 2010; accepted January 8, 2010.
- DYT1 dystonia;
- no-net flux microdialysis;
J. Neurochem. (2010) 10.1111/j.1471-4159.2010.06590.x
Early onset torsion dystonia (DYT1), the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein, torsinA. We previously examined the effect of the human mutant torsinA on striatal dopaminergic function in a conventional transgenic mouse model of DYT1 dystonia (hMT1), in which human mutant torsinA is expressed under the cytomegalovirus promotor. Systemic administration of amphetamine did not increase dopamine (DA) release as efficiently in these mice as compared with wild-type transgenic and non-transgenic mice. We, now, studied the contribution of the DA transporter (DAT) to amphetamine-induced DA release in hMT1 transgenic mice using in vivo no-net flux microdialysis. This method applies different concentrations of DA through the microdialysis probe and measures DA concentration at the output of the probe following an equilibrium period. The slope (extraction fraction) is the measure of the DAT activity in vivo. The slope for hMT1 transgenic mice was 0.58 ± 0.07 and for non-transgenic animals, 0.87 ± 0.06 (p < 0.05). We further investigated the efficacy of nomifensine (a specific DAT inhibitor) in inhibiting amphetamine-induced DA release. Local application of nomifensine 80 min before the systemic application of amphetamine inhibited DA release in both transgenic mice and their non-transgenic littermates. The efficiency of the inhibition appeared to be different, with mean values of 48% for hMT1 transgenic mice versus 84% for non-transgenic littermates. Moreover, we have evaluated basal and amphetamine-induced locomotion in hMT1 transgenic mice compared with their non-transgenic littermates, using an O-maze behavioral chamber. Basal levels of locomotion in the hMT1 transgenic mice showed that they moved much less than their non-transgenic littermates (0.9 ± 0.3 m for transgenic mice vs. 2.4 ± 0.7 m for non-transgenic littermates, p < 0.05). This relative reduction in locomotion was also observed following amphetamine administration (48.5 ± 6.7 m for transgenics vs. 73.7 ± 9.8 m for non-transgenics, p < 0.05). These results support the finding that there are altered dynamics of DA release and reuptake in hMT1 transgenic mice in vivo, with DAT activity is reduced in the presence of mutant torsinA, which is consistent with behavioral consequences such as reduced locomotion and (previously described) abnormal motor phenotypes such as increased hind-base width and impaired performance on the raised-beam task. These data implies that altered DAT function may contribute to impaired DA neurotransmission and clinical symptoms in human DYT1 dystonia.