5-HT4 receptor-mediated modulation of 5-HT release in the rat hippocampus in vivo

1. In the present study, the ability of the 5-hydroxytryptamine, receptor (5-HT4 receptor) to modulate the release of 5-HT in the hippocampus of freely-moving rats was investigated by the in vivo microdialysis technique. 2. The 5-HT4 receptor agonist, renzapride (1.0-100 microM, administered via the microdialysis probe) increased extracellular hippocampal levels of 5-HT in concentration-dependent manner (approximately 200% maximal increase). The ability of renzapride (100 microM, administered via the microdialysis probe) to elevate extracellular levels of 5-HT remained in the presence of the selective 5-HT reuptake blocker, paroxetine (1.0 microM, administered via the microdialysis probe). Furthermore, another 5-HT4 receptor agonist 5-methoxytryptamine (5-MeOT; 10 microM, administered via the microdialysis probe, in the presence of the non-5-HT4 5-HT receptor antagonists pindolol (10 microM) and methysergide (10 microM)) maximally elevated extracellular levels of 5-HT by approximately 450% in the rat hippocampus. The elevation of extracellular 5-HT levels induced by either renzapride (100 microM) or 5-MeOT (10 microM) was completely prevented by combined administration of the selective 5-HT4 receptor antagonist, GR113808 (100 nM, administered via the microdialysis probe). GR113808 (100 nM, administered via the microdialysis probe) administered alone, however, reduced extracellular hippocampal 5-HT levels by some 60%. 3. Systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT (0.1 mg kg-1, s.c.) reduced extracellular levels of 5-HT in the rat hippocampus by approximately 40%. Prior administration of 8-OH-DPAT (0.1 mg kg-1, s.c.), with an associated reduction of extracellular hippocampal 5-HT levels by approximately 40-50%, however, failed to prevent a subsequent elevation of extracellular levels of 5-HT induced by renzapride (100 microM, administered via the microdialysis probe). 4. Systemic administration of the 5-HT4 receptor agonist, renzapride (0.25 and 1.0 mg kg-1, i.p.) increased extracellular levels of 5-HT in the hippocampus in a dose-dependent manner. The higher dose of renzapride increasing extracellular 5-HT levels by some 200%. The selective 5-HT4 receptor antagonist, GR125487D (1.0-100 micrograms kg-1, i.p.) caused a dose-dependent reduction in extracellular levels of 5-HT in the hippocampus (maximally approximately 80% reduction). Prior administration of GR125487D (10 micrograms kg-1, i.p.) prevented the elevation of extracellular levels of 5-HT induced by renzapride (1.0 mg kg-1, i.p.). 5. In conclusion, the present study provides evidence that activation of the 5-HT4 receptor facilitates 5-HT release in the rat hippocampus in vivo.