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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.

Lorrain DS, Baccei CS, Correa LD, Bristow LJ

Department of Pharmacology, Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA. daniel_lorrain@merck.com

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.

Published 28 April 2005 in Neuropharmacology, 48(7): 927-35.
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