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

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Abstract
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 selective 5-HT4 receptor antagonist, GR113808 (1 μm) and the renzapride (100 μm)-induced response was also completely prevented by the non-selective protein kinase A inhibitor, H7 (1 μm). In this in vivo preparation, both GR113808 (1 μm) and H7 (1 μm), when perfused alone, reduced extracellular levels of dopamine. 5 In conclusion, the present study provides evidence that the 5-HT4 receptor facilitates rat striatal dopamine release in vitro and in vivo.