Modulation of NMDA receptor activity by dopamine receptors in the rat striatum

• Main Author: Tong, Huaxia
• Published: University College London (University of London) 2006
• Subjects: 612.8042
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427793

NMDA receptors are of particular importance in the control of synaptic strength and integration of synaptic activity. Dopamine receptor modulation of NMDA receptors in the striatum may influence the efficacy of synaptic transmission in the cortico-striatal pathway (Calabresi et al., 2000c Centonze et al., 2003) and if so, this modulation will be lost in Parkinson's disease. This change may be an important factor in the changes in the basal ganglia neural network that occur in Parkinson's Disease. In this thesis I have studied dopamine D1 and D2 receptor modulation of NMDA receptors in medium spiny neurons of 7-21 day old rat striatum. The dopamine D1 receptor agonist, SKF-82958, significantly decreased rat striatal NMDA receptor currents in patch-clamp whole-cell recordings from 7 day old rats. This inhibition was not abolished by application of a G protein inhibitor (GDP-p-S) or irreversible activator (GTP-y-S) suggesting a G protein-independent mechanism. In addition, intracellular application of protein tyrosine kinase inhibitors (lavendustin A or PP2) abolished D1 inhibition of NMDA currents. Functional NR2A receptors were absent in 7 day old rat striatum according to my experiments. Single-channel recordings showed that direct D1 receptor inhibition of NMDA receptors can not be observed in isolated membrane patches, which may indicate that D1 inhibition in whole-cell recordings is mediated by a change in NMDA receptor trafficking. Consistent with this hypothesis, intracellular application of a dynamin inhibitory peptide (QVPSRPNRAP) abolished D1 inhibition of NMDA receptor currents. I therefore conclude that a tyrosine kinase-dependent alteration of NMDA receptor trafficking underlies D1 dopamine receptor-mediated down-regulation of NMDA receptor currents in the striatum. The D2 class dopamine receptor agonist, quinpirole, significantly inhibited the NMDAR responses at 1 uM, but at a lower concentration (40 nM) there was no significant effect in 7 day old rat striatum. Replacement of GTP with GDP-P-S in the pipette solution abolished the inhibition induced by 1 uM quinpirole suggesting a G protein-dependent mechanism underlies the D2 family dopamine receptor modulation of NMDA receptors in the striatum.