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

• Published in: British journal of pharmacology Vol. 117; no. 7; pp. 1475 - 1480
• Main Authors: Ge, Jian, Barnes, Nicholas M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.1996; Nature Publishing
• Subjects: 5‐HT release; 5‐Hydroxytryptamine4 receptor; Animals; benzamides; Benzamides - pharmacology; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell receptors; Cell structures and functions; Fundamental and applied biological sciences. Psychology; Hippocampus - metabolism; in vivo microdialysis; Indoles - pharmacology; Male; Microdialysis; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); rat hippocampus; Rats; Receptors, Serotonin - drug effects; Receptors, Serotonin - physiology; Receptors, Serotonin, 5-HT4; Serotonin - metabolism; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology; Sulfonamides - pharmacology; Vertebrata; Mammalia; Serotoninergic transmission; Rat; Serotonin; Animal; Modulation; Rodentia; 5-HT4 receptor; Central nervous system; Hippocampus
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15309.x

1 In the present study, the ability of the 5‐hydroxytryptamine4 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 μm, administered via the microdialysis probe) increased extracellular hippocampal levels of 5‐HT in a concentration‐dependent manner (approximately 200% maximal increase). The ability of renzapride (100 μm, 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 μm, administered via the microdialysis probe). Furthermore, another 5‐HT4 receptor agonist 5‐methoxytryptamine (5‐MeOT; 10 μm, administered via the microdialysis probe, in the presence of the non‐5‐HT4 5‐HT receptor antagonists pindolol (10 μm) and methysergide (10 μm)) 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 μm) or 5‐MeOT (10 μm) 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 μm, 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 μg 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 μg 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.