The alpha 2-adrenoceptor antagonist idazoxan is an agonist at 5-HT1A autoreceptors modulating serotonin synthesis in the rat brain in vivo.
The in vivo effects of the alpha 2-adrenoceptor idazoxan, rauwolscine and phentolamine on alpha 2-auto/heteroreceptors and 5-HT1A autoreceptors modulating the synthesis of dopa/noradrenaline and 5-HTP/serotonin were assessed in rats, using the accumulation of dopa and 5-HTP after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation. The acute administration of idazoxan (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-autoreceptors. However, idazoxan did not increase the synthesis of 5-HTP in these brain regions, as it would have been expected by the concurrent blockade of alpha 2-heteroreceptors on serotonergic terminals. Instead, idazoxan 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 results were obtained for rauwolscine. Pre-treatment of rats with the selective 5-HT1A receptor antagonist WAY100135 (10 mg/kg) fully antagonized the inhibitory effects of idazoxan (10 mg/kg) on 5-HTP synthesis, but it did not prevent the stimulatory effects of idazoxan on dopa synthesis. The results indicate that idazoxan is a potent and specific agonist at 5-HT1A autoreceptors modulating brain serotonin synthesis in vivo.
Lladó
J
J
Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain.
Esteban
S
S
García-Sevilla
J A
JA
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects*; D019329:Idazoxan / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
D017366:Serotonin Receptor Agonists; D015016:Yohimbine; D012701:Serotonin; D004295:Dihydroxyphenylalanine; D019329:Idazoxan