期刊
JOURNAL OF NEUROPHYSIOLOGY
卷 98, 期 1, 页码 423-432出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/jn.00971.2006
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资金
- NIMH NIH HHS [MH044894] Funding Source: Medline
- NINDS NIH HHS [NS33538] Funding Source: Medline
Altered corticostriatal neurotransmission and modulation in dopamine transporter knockdown mice. J Neurophysiol 98: 423-432, 2007. First published May 23, 2007; doi: 10.1152/ jn. 00971.2006. Dopamine (DA) modulates glutamate neurotransmission in the striatum. Abnormal DA modulation has been implicated in neurological and psychiatric disorders. The development of DA transporter knock-down (DAT-KD) mice has permitted modeling of these disorders and has shed new light on DA modulation. DAT-KD mice exhibit increased extracellular DA, hyperactivity, and alterations in habituation. We used whole cell patch-clamp recordings from visually identified striatal neurons in slices to examine the effects of DAT- KD on corticostriatal transmission. Electrophysiological recordings from medium- sized spiny neurons in the dorsal striatum revealed alterations in both amplitude and frequency, of spontaneous glutamate receptor- mediated synaptic currents in cells from DAT- KD mice. Furthermore, kinetic analyses revealed that these currents had shorter half- amplitude durations and faster decay times. In contrast, GABA- receptor - mediated synaptic currents were not altered. Striatal neurons from DAT- KD mice also responded differently to amphetamine, cocaine, and DA D2- receptor agonists or antagonists compared with wildtype ( WT) littermate controls. In WTs amphetamine and cocaine reduced the frequency of spontaneous glutamate currents and these effects appeared to be mediated by activation of D2 receptors. In contrast, in DAT-KD mice either no changes or only small increases in frequency occurred. D2-receptor agonists or antagonists also had opposing effects in WT and DAT-KD mice. Together, these results indicate that chronically increased extracellular DA produces long-lasting changes in corticostriatal communication that may be mediated by changes in D2-receptor function. These findings have implications for understanding mechanisms underlying attention deficit hyperactivity disorder and Tourette's syndrome and may provide insights into novel therapeutic approaches.
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