Comparison of the effects of diazepam, the CRF1 antagonist CP-154,526 and the group II mGlu receptor agonist LY379268 on stress-evoked extracellular norepinephrine levels

Neuropharmacology. 2005 Jun;48(7):927-35. doi: 10.1016/j.neuropharm.2004.12.022.


The present study used an elevated platform procedure to investigate the effects of diazepam, a CRF1 antagonist CP-154,526 and a group II mGlu2/3 receptor agonist LY379268 on stress-evoked increase in extracellular norepinephrine (NE). Pretreatment with either diazepam (1 mg/kg, i.p.), CP-154,526 (20 mg/kg, i.p.) or LY379268 (1, 3 and 10 mg/kg, p.o.) significantly reduced platform stress-evoked NE. Interestingly, at the highest dose tested (10 mg/kg) LY379268 caused a marked increase in baseline NE levels. We tested whether this effect would diminish after repeated dosing. In contrast to acute administration, a challenge injection of LY379268 after repeated dosing (10 mg/kg x days) did not alter basal NE. Importantly, although less effective, LY379268 still significantly reduced stress-evoked NE. We further show that this increase in basal NE may involve mGlu2/3 receptor regulation of the GABAergic system. To this end, administration of the GABAB agonist, baclofen (4 mg/kg, i.p.), 2 h after dosing with LY379268, reversed the increase in baseline NE. These data suggest that, like diazepam and CP-154,526, group II mGlu2/3 receptor agonists can attenuate stress-evoked increase in extracellular NE in the rat prefrontal cortex. In addition they reveal a 'stress-like' increase in NE after high doses of LY379268 which may reflect mGlu3 receptor modulation of GABAergic transmission.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acids / pharmacology*
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Diazepam / pharmacology*
  • Extracellular Fluid / drug effects
  • Extracellular Fluid / metabolism
  • Male
  • Norepinephrine / metabolism*
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / metabolism
  • Stress, Physiological / metabolism


  • Amino Acids
  • Bridged Bicyclo Compounds, Heterocyclic
  • CP 154526
  • LY 379268
  • Pyrimidines
  • Pyrroles
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • CRF receptor type 1
  • Diazepam
  • Norepinephrine