Ability of 5‐HT4 receptor ligands to modulate rat striatal dopamine release in vitro and in vivo

1 The ability of 5‐HT4 (5‐hydroxytryptamine4) receptor ligands to modify dopamine release from rat striatal slices in vitro and in the striatum of freely moving rats was assessed by the microdialysis technique. 2 The release of dopamine from slices of rat striatum continually perfused with Krebs buffer was enhanced by 5‐HT4 receptor agonists; 5‐HT (10 μm), 5‐methoxytryptamine (5‐MeOT; 10 μm), renzapride (10 μm) and (S)‐zacopride (10 μm) maximally increased dopamine release by 133 ± 5, 214 ± 25, 232 ± 29 and 264 ± 69%, respectively (mean ± s.e.mean, n = 3–8). The drug‐induced responses were maximal within the first 2 min of drug application, and subsequently declined. The non‐selective 5‐HT3/5‐HT4 receptor antagonist, SDZ205‐557 (10 μm), failed to modify basal dopamine release from striatal slices but completely antagonized the (S)‐zacopride (10 μm)‐induced increase in dopamine release. 3 To allow faster drug application, the modulation of dopamine release from rat striatal slices in a static release preparation was also investigated. The 5‐HT4 receptor agonist, renzapride (10 μm) also enhanced dopamine release in this preparation (maximal increase = 214 ± 35%, mean ± s.e.mean, n = 14), whilst a lower concentration of renzapride (3 μm) was less effective. The renzapride‐induced response was maximal within the first 2 min of drug application, before declining. In this preparation, the stimulation of dopamine release by renzapride (10 μm), was completely antagonized by the selective 5‐HT4 receptor antagonist, 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 μm). 4 In vivo microdialysis studies demonstrated that the 5‐HT4 receptor agonists, 5‐MeOT (10 μm), renzapride (100 μm) and (S)‐zacopride (100 μm) maximally elevated extracellular 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 μm) was less effective. The elevation of extracellular striatal dopamine levels induced by either renzapride (100 μm) or (S)‐zacopride (100 μm) were completely antagonized by the non‐selective 5‐HT3/5‐HT4 receptor antagonist, SDZ205‐557 (100 μm). In addition, the elevation of extracellular levels of dopamine induced by either 5‐MeOT (10 μm) or renzapride (100 μm) was completely prevented by the selectiv