Regulators of G-protein signaling 4: modulation of 5-HT1A-mediated neurotransmitter release in vivo

Brain Res. 2004 Oct 1;1022(1-2):214-20. doi: 10.1016/j.brainres.2004.06.073.

Abstract

Regulators of G-protein signaling (RGS) play a key role in the signal transduction of G-protein-coupled receptors (GPCRs). Specifically, RGS proteins function as GTPase accelerating proteins (GAPs) to dampen or "negatively regulate" GPCR-mediated signaling. Our group recently showed that RGS4 effectively GAPs Galpha(i)-mediated signaling in CHO cells expressing the serotonin-1A (5-HT(1A)) receptor. However, whether a similar relationship exists in vivo has yet to be identified. In present studies, a replication-deficient herpes simplex virus (HSV) was used to elevate RGS4 mRNA in the rat dorsal raphe nuclei (DRN) while extracellular levels of 5-HT in the striatum were monitored by in vivo microdialysis. Initial experiments conducted with noninfected rats showed that acute administration of 8-OH-DPAT (0.01-0.3 mg/kg, subcutaneous [s.c.]) dose dependently decreased striatal levels of 5-HT, an effect postulated to result from activation of somatodendritic 5-HT(1A) autoreceptors in the DRN. In control rats receiving a single intra-DRN infusion of HSV-LacZ, 8-OH-DPAT (0.03 mg/kg, s.c.) decreased 5-HT levels to an extent similar to that observed in noninfected animals. Conversely, rats infected with HSV-RGS4 in the DRN showed a blunted neurochemical response to 8-OH-DPAT (0.03 mg/kg, s.c.); however, increasing the dose to 0.3 mg/kg reversed this effect. Together, these findings represent the first in vivo evidence demonstrating that RGS4 functions to GAP Galpha(i)-coupled receptors and suggest that drug discovery efforts targeting RGS proteins may represent a novel mechanism to manipulate 5-HT(1A)-mediated neurotransmitter release.

Publication types

  • Comparative Study

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / administration & dosage
  • Animals
  • Corpus Striatum / metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Gene Expression Regulation / physiology*
  • In Situ Hybridization / methods
  • Male
  • Microdialysis / methods
  • Neurotransmitter Agents / classification
  • Neurotransmitter Agents / metabolism*
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • Raphe Nuclei / metabolism*
  • Raphe Nuclei / virology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / physiology*
  • Serotonin / metabolism
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / administration & dosage
  • Signal Transduction / physiology*
  • Simplexvirus / physiology
  • Time Factors

Substances

  • Neurotransmitter Agents
  • Piperazines
  • Pyridines
  • RGS Proteins
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • RGS4 protein
  • Serotonin
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin