ABILITY OF 5-HT4 RECEPTOR LIGANDS TO MODULATE RAT STRIATAL DOPAMINE RELEASE IN-VITRO AND IN-VIVO

1 The ability of 5-HT4 (5-hydroxytryptamine(4)) receptor ligands to mo dify dopamine release from rat striatal slices in vitro and in the str iatum of freely moving rats was assessed by the microdialysis techniqu e. 2 The release of dopamine from slices of rat striatum continually p erfused with Krebs buffer was enhanced by 5-HT4 receptor agonists; 5-H T (10 mu M), 5-methoxytryptamine (5-MeOT; 10 mu M), renzapride (10 mu M) and (S)-zacopride (10 mu M) maximally increased dopamine release by 133+/-5, 214+/-25, 232+/-29 and 264+/-69%, respectively (mean+/-s.e.m ean, n=3-8). The drug-induced responses were maximal within the first 2 min of drug application, and subsequently declined. The non-selectiv e 5-HT3/5-HT4 receptor antagonist, SDZ205-557 (10 mu M), failed to mod ify basal dopamine release from striatal slices but completely antagon ized the (S)-zacopride (10 mu M)-induced increase in dopamine release. 3 To allow faster drug application, the modulation of dopamine releas e from rat striatal slices in a static release preparation was also in vestigated. The 5-HT4 receptor agonist, renzapride (10 mu M) also enha nced dopamine release in this preparation (maximal increase=214+/-35%, mean+/-s.e.mean, n = 14), whilst a lower concentration of renzapride (3 mu M) was less effective. The renzapride-induced response was maxim al within the first 2 min of drug application, before declining. In th is preparation, the stimulation of dopamine release by renzapride (10 mu M), was completely antagonized by the selective 5-HT4 receptor anta gonist, GR113808 (100 nM). In addition, both the Na+ channel blocker, tetrodotoxin (100 nM) and the non-selective protein kinase A inhibitor , H7 (100 nM) completely prevented the stimulation of dopamine release induced by renzapride (10 mu M) 4 In vivo microdialysis studies demon strated that the 5-HT4 receptor agonists, 5-MeOT (10 mu M), renzapride (100 mu M) and (S)-zacopride (100 mu M) maximally elevated extracellu lar levels of dopamine in the striatum by 220+/-20, 161+/-10 and 189+/ -53%, respectively (mean+/-s.e.mean, n=5-9). A lower concentration of renzapride (10 mu M) was less effective. The elevation of extracellula r striatal dopamine levels induced by either renzapride (100 mu M) or (S)-zacopride (100 mu M) were completely antagonized by the non-select ive 5-HT3/5-HT4 receptor antagonist, SDZ205-557 (100 mu M). In additio n, the elevation of extracellular levels of dopamine induced by either 5-MeOT (10 mu M) or renzapride (100 mu M) was completely prevented by the selective 5-HT4 receptor antagonist, GR113808 (1 mu M) and the re nzapride (100 mu M)-induced response was also completely prevented by the non-selective protein kinase A inhibitor, H7 (1 mu M). In this in vivo preparation, both GR113808 (1 mu M) and H7 (1 mu M), when perfuse d alone, reduced extracellular levels of dopamine. 5 In conclusion, th e present study provides evidence that the 5-HT4 receptor facilitates rat striatal dopamine release in vitro and in vivo.