Striatal dopamine D1 receptors have been reported to increase (Flores-Hernandez et al. 2002), or attenuate NMDA receptor currents (Lee, et al. 2002). In our experiments we have used whole cell patch-clamp recordings from medium spiny neurons in 300µm thick striatal slices from humanely killed 7 day old rats to investigate the mechanism of NMDA receptor modulation.

NMDAR responses were evoked by 10 µM NMDA and 10 µM glycine. In the presence of TTX (100 nM) to block action potentials and the D2 receptor antagonist spiperone (2 nM) with ATP (1 mM) and GTP (1 mM) in the pipette solution. The D1 receptor agonist, SKF-82958 (20 nM), significantly (paired t test, P < 0.05) decreased the NMDA whole-cell current from 249 ± 36 pA to 153 ± 31 pA (mean ± S.E.M., n = 10 cells). Replacement of intracellular GTP with GDP-β-S (0.5 mM) did not prevent inhibition (control: 162 ± 34 pA, SKF-82958: 74 ± 12 pA, n = 9 cells) suggesting D1 inhibition is not dependent on G protein activation. These results are consistent with those of Lee et al. (2002) who demonstrated a direct inhibitory interaction between the C-termini of the D1 receptor and the NMDA receptor NR2A subunit. However protein immunohistochemistry (Portera-Cailliau et al. 1996) and in situ mRNA hybridization (Monyer et al. 1994) show a lack of NR2A expression in 7 day old rat striatum. We therefore tested for the presence of functional NR2A-containing receptors (Paoletti et al. 1997) using ZnCl2 (100 nM) or for the presence of tonic Zn inhibition using the Zn chelating agent TPEN (1µM) (control: 194 ± 20 pA, ZnCl2: 198 ± 15 pA, TPEN: 181 ± 11 pA, n = 5 cells).

These results suggest an absence of functional NR2A receptors in 7 day old rat striatum and therefore that there may be an NR2A-independent mechanism mediating direct, G protein-independent, inhibition of NMDA receptors in the neonatal rat striatum.

This work was supported by the Wellcome Trust. H.T. is funded by a UCL Graduate School Research Scholarship