title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA. daniel_lorrain@merck.com
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lorrain
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Baccei
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Correa
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C101628:CP 154526; C118218:LY 379268; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D000099052:CRF Receptor, Type 1; D003975:Diazepam; D009638:Norepinephrine