ABILITY OF ANGIOTENSIN-II TO MODULATE STRIATAL DOPAMINE RELEASE VIA THE AT(1) RECEPTOR IN-VITRO AND IN-VIVO

1 The ability of angiotensin II to modulate dopamine release from rat striatal slices in vitro and in the intact rat striatum in vivo was as sessed by the microdialysis technique. 2 In slices of rat striatum, an giotensin II (0.1-1.0 mu M) induced a concentration-related increase i n endogenous dopamine release which was maximal (approximately 250% ab ove basal levels) within the first 2-4 min of agonist application and subsequently declined to near basal values. The angiotensin II-induced increase in dopamine release was Ca2+-dependent and was completely an tagonized by the selective AT(1) receptor antagonist, losartan (1.0 mu M). In contrast, the AT(2) receptor antagonist, PD123177 (1.0 mu M) f ailed to modify the angiotensin II-induced response. Neither antagonis t alone modified basal dopamine release from striatal slices. 3 In fre ely moving rats, angiotensin II (1.0-10 mu M; administered via the mic rodialysis probe) induced a concentration-related increase in extracel lular levels of dopamine which was maximal (approximately 150% above b asal levels) within 20-40 min of agonist application and subsequently declined. The angiotensin II (10 mu M)-induced increase in extracellul ar levels of dopamine was completely antagonized by the AT(1) receptor antagonist, losartan (0.1-1.0 mu M; administered via the microdialysi s probe) but not by the AT(2) receptor antagonist, PD123177 (1.0 mu M; administered via the microdialysis probe). Neither antagonist alone m odified basal extracellular levels of dopamine. 4 Homogenate radioliga nd binding studies with [I-125]-angiotensin II (0.1 nM) identified rel atively low levels of specific binding sites in rat striatal homogenat es compared to homogenates of pyriform cortex (51.3+/-9.2 and 651.3+/- 55.1 fmol g(-1) wet weight, respectively, mean+/-s.e.mean, n=3; non-sp ecific binding defined by unlabelled angiotensin II). The majority of the specific [I-125]-angiotensin II (0.1 nM) binding in the striatal a nd pyriform cortex homogenates was sensitive to the selective AT(1) re ceptor antagonist, losartan (1.0 mu M). 5 In conclusion, the present s tudy provides direct evidence that angiotensin II acting via the AT(1) receptor subtype facilitates the release of dopamine in the rat stria tum in vitro and in vivo. This receptor-mediated response may account for the modulation of dopamine-mediated behavioural responses by antag onists of the AT(1) receptor and inhibitors of angiotensin converting enzyme.