THE ALPHA(2)-ADRENOCEPTOR ANTAGONIST IDAZOXAN IS AN AGONIST AT 5-HT1AAUTORECEPTORS MODULATING SEROTONIN SYNTHESIS IN THE RAT-BRAIN IN-VIVO

The in vivo effects of the alpha(2)-adrenoceptor antagonists idazoxan, rauwolscine and phentolamine on alpha(2)-auto/heteroreceptors and 5-H T1A autoreceptors modulating the synthesis of dopa/noradrenaline and 5 -HTP/serotonin were assessed in rats, using the accumulation of dopa a nd 5-HTP after decarboxylase inhibition as a measure of the rate of ty rosine and tryptophan hydroxylation. The acute administration of idazo xan (0.1-40 mg/kg) induced a pronounced dose-dependent increase in the synthesis of dopa in the cerebral cortex (22-86%) and hippocampus (8- 80%), as a consequence of the powerful blockade of alpha(2)-autorecept ors. However, idazoxan did not increase the synthesis of 5-HTP in thes e brain regions, as it would have been expected by the concurrent bloc kade of alpha(2)-heteroreceptors on serotonergic terminals. Instead, i dazoxan decreased the synthesis of 5-HTP in the cerebral cortex (13-33 %) and hippocampus (25-48%), suggesting that these inhibitory effects were mediated through activation of 5-HT1A autoreceptors. Similar resu lts were obtained for rauwolscine. Pre-treatment of rats with the sele ctive 5-HT1A receptor antagonist WAY100135 (10 mg/kg) fully antagonize d the inhibitory effects of idazoxan (10 mg/kg) on 5-HTP synthesis, bu t it did not prevent the stimulatory effects of idazoxan on dopa synth esis. The results indicate that idazoxan is a potent and specific agon ist at 5-HT1A autoreceptors modulating brain serotonin synthesis in vi vo.