THE ALPHA(2)-ADRENOCEPTOR ANTAGONIST ORG-3770 ENHANCES SEROTONIN TRANSMISSION IN-VIVO

The antidepressant properties of Org 3770 (1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine) may be mediated via blockade of auto and hetero alpha-2-adrenoceptors. On-line microdialysis studies in freely moving rats showed Org 3770 (2 mg/kg s.c.) to increase hippocampal 5-HT (5-hydroxytryptamine) and dihydroxyphenyl acetic acid (DOPAC) - a measure of noradrenergic activity - by approximately 80%. The increase in DOPAC is probably caused by blockade of alpha(2)-autoreceptors on noradrenergic terminals. Indirect alpha(1),-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory alpha(2)-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT.