5-HT1B receptor-mediated presynaptic inhibition at the calyx of Held of immature rats

Eur J Neurosci. 2006 Oct;24(7):1946-54. doi: 10.1111/j.1460-9568.2006.05063.x.

Abstract

5-hydroxytryptamine (5-HT) inhibits transmitter release via activating GTP-binding proteins, but the target of 5-HT receptors in the nerve terminal is not determined. We addressed this question at the calyx of Held synapse in the brainstem slice of immature rats. Bath-application of 5-HT attenuated the amplitude of nerve-evoked excitatory postsynaptic currents (EPSCs) associated with an increase in the paired-pulse ratio, whereas it had no effect on the amplitude of spontaneous miniature EPSCs. The 5-HT1B receptor agonist CP93129 mimicked the inhibitory effect of 5-HT, but the 5-HT1A agonist (R)-(+)-8-hydroxy-DPAT (8-OHDPAT) had no effect. The 5-HT1B receptor antagonist NAS-181 blocked the inhibitory effect of 5-HT. These results suggest that 5-HT activated 5-HT1B receptors in calyceal nerve terminals, thereby inhibiting transmitter release. In direct whole-cell recordings from calyceal nerve terminals, 5-HT attenuated voltage-dependent Ca2+ currents, but had no effect on voltage-dependent K+ currents. When EPSCs were evoked by presynaptic Ca2+ currents during simultaneous pre- and postsynaptic recordings, the magnitude of the 5-HT-induced inhibition of Ca2+ currents fully explained that of EPSCs. Upon repetitive applications, 5-HT showed tachyphylaxis, with its effect on both EPSCs and presynaptic Ca2+ currents becoming weaker in the second application. 1,2-bis(o-aminophenoxy)ethane-N-N'-N'-N'-tetraacetic acid (BAPTA; 10 mm) loaded into the nerve terminal abolished this tachyphylaxis. The presynaptic inhibitory effect of 5-HT was prominent at postnatal day 5, but became weaker as animals matured. We conclude that activation of 5-HT1B receptors inhibits voltage-gated Ca2+ channels, thereby inhibiting transmitter release at immature calyceal nerve terminals, and that 5-HT1B receptors undergo Ca2+-dependent tachyphylaxis on repetitive activations.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Baclofen / pharmacology
  • Benzopyrans / pharmacology
  • Brain Stem / cytology*
  • Brain Stem / growth & development
  • Calcium / pharmacology
  • Drug Interactions
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Electric Stimulation / methods
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Excitatory Postsynaptic Potentials / radiation effects
  • GABA Agonists / pharmacology
  • In Vitro Techniques
  • Morpholines / pharmacology
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Neurons / cytology*
  • Neurons / physiology
  • Patch-Clamp Techniques / methods
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / physiology*
  • Pyridines / pharmacology
  • Pyrroles / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1B / physiology*
  • Serotonin / pharmacology
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Time Factors

Substances

  • 2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine
  • Benzopyrans
  • GABA Agonists
  • Morpholines
  • Pyridines
  • Pyrroles
  • Receptor, Serotonin, 5-HT1B
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one
  • Serotonin
  • Egtazic Acid
  • Baclofen
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
  • Calcium