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Activation of dopamine D3 receptors induces c-fos expression in primary cultures of rat striatal neurons.

Morris BJ, Newman-Tancredi A, Audinot V, Simpson CS, Millan MJ.
J Neurosci Res. 2000 Mar 15;59(6):740-9.

A modulation of the expression of immediate-early genes (IEGs) such as c-fos is likely involved in the long-term influence of dopaminergic ligands on the activity of basal ganglia neurons. The roles of individual dopamine receptor types in this regard remain unclear, and the present study employed primary cultures of rat striatal neurons to examine the potential modulation of c-fos expression by D3 receptors. Neurons were treated with the preferential D3 receptor agonists, (+/-)-7-OH-DPAT and PD128,907, which showed, respectively, 16-fold and 56-fold selectivity for recombinant rat D3 vs. D2 receptors (Ki values, rD2/rD3 = 59.5/3.7 nM and 251/4.5 nM, respectively). At concentrations of 3 and 30 nM, respectively, (+/-)-7-OH-DPAT and PD128,907 significantly increased the expression of c-fos mRNA. The action of (+/-)-7-OH-DPAT was expressed stereospecifically; its (+)-isomer (Ki values, D3/D2 = 1.6/56.7 elicited a 26% +/- 7.6% increase in c-fos expression whereas its (-)-isomer (Ki values, D3/D2 = 59/1,060 nM) was ineffective. Further, stimulation of c-fos mRNA expression by PD128,907 (20 nM) was markedly and significantly (P<0.05) attenuated (-91.8% +/- 5.3%) by 30 nM of the selective D(3) receptor antagonist, (+)-S 14297 (Ki values, D3/D2 = 11/401 nM). In contrast, the action of PD128,907 was significantly less affected (-24.5% +/- 7.8%) by 30 nM of its less active distomer, (-)-S17777 (Ki values, D3/D2 = 294/3,191 nM). An examination of the concentration-response relationship revealed that (+/-)-7-OH-DPAT and PD 128,907 both produced bell-shaped dose-response curves for c-fos induction. The sequential activation of D2 receptors-which inhibit striatal c-fos expression (Simpson and Morris [1995] Neuroscience 68:97-106)-by higher concentrations of (+/-)-7-OH-DPAT and PD128,907 is presumably involved in the inflexion at higher doses. In conclusion, the present data demonstrate that activation of D3 receptors results in a selective induction of c-fos mRNA expression in cultured striatal neurons. These data show that neuronal D3 receptors control the expression of IEGs and suggest that D3 receptors may mediate long-term adapative changes in the activity of neurons in the basal ganglia.