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SCH23390 attenuates A1 receptor-mediated inhibition of electrically evoked dopamine release from rat striatal slices Adenosine receptors are highly expressed both postsynaptically and presynaptically in the striatum. Studies using microdialysis to measure extracellular rat striatal dopamine release in vivo have shown that CPA, an A1 receptor agonist, and CGS 21680, an A2 receptor agonist, diminished methamphetamine-induced dopamine overflow in a dose-dependent manner ( Golembiowska et al .,1998). Dopamine release is also regulated by presynaptic dopamine receptors and interactions between adenosine and dopamine receptors have been well documented (Ferre et al. 1997). The aim of the present study was to investigate whether adenosine-dopamine interactions play a role in regulating electrically evoked dopamine release from rat striatal slices. The release of dopamine from male Wistar rat striatal slices (30-40 g) was measured using fast cyclic voltammetry (FCV; Kruk, et al., 1995). Single pulse stimulation (0.1ms; 10 V) was applied every 5 min over a 2 hr period ( 0.09±0.02 m M dopamine, per stimulation; 1.0±0.1 s reuptake time, n=8). D1 dopamine receptor competition binding experiments were carried out using 3HSCH23390 as radioligand. Data are expressed as mean±sem. IC50 values were determined using PRISM. The D2 receptor agonist quinpirole inhibited single pulse stimulated dopamine release (94.0±4.2 % inhibition at 0.1 μM n=4).The D2 receptor antagonist metoclopramide (0.3 μM) had no effect on single pulse dopamine release but increased 10 pulse (5 Hz) stimulated dopamine release (178.6 ± 39.4% control, n=4). Perfusion with the A 1 receptor agonist CPA inhibited dopamine release in a concentration dependent manner (55.7±3.7% maximum inhibition with 10μM CPA, IC50 5.19 x 10-7 M, n=9). Perfusion of the A1 receptor antagonist DPCPX had no effect on stimulated dopamine release but attenuated the inhibitory effect of CPA (IC50 5.12 x 10-6 M, n=5). The D 1 receptor antagonist, SCH23390 (3 μM), attenuated theninhibitory effect of CPA on dopamine release (IC50 8.26 X 10 -6, n=5) The presence of metoclopramide (0.3 μM) did not alter the effect of CPA on dopamine release (IC50 3.89 x 10 -7 M, n=4). Neither CPA nor DPCPX (10-9-10-5 M) competed with 3HSCH23390 binding to rat striatal slices, indicating that these ligands do not interact directly with D1 receptors. In summary, we have shown that A1 receptor activation inhibits evoked dopamine release by a mechanism that is independent of D2 receptor activity. However, block of D1 receptors attenuated the A1 receptor mediated-inhibition of dopamine release. Adenosine-dopamine interactions may provide new therapeutic approaches for basal ganglia disorders. This work was supported by the Higher Education Authority of Ireland.
Ferre et al., (1997). Trends Neurosci. 20, 482-487. |
