3-Methoxytyramine, an extraneuronal dopamine metabolite plays a physiological role in the brain as an inhibitory regulator of catecholaminergic activity

3-Methoxytyramine (3-MT), an extraneuronal metabolite of dopamine, present in the synaptic cleft at a very low amount (low nanomolar range). comparable to dopamine concentration, is generally regarded as a biologically inactive compound. We have shown in this study that 3-MT binds to the rat noradrenergic cortical alpha(1) and striatal dopamine D-1 and D-2 receptors in nanomolar concentration range, and to cortical alpha(2) adrenoceptor at low micromolar concentration. Bilateral intrastriatal injections of 3-MT (0.25 mu mol in 0.5 mu l) did not affect significantly locomotor activity in naive rats but strongly antagonized amphetamine-induced (1 mg/kg s.c.) hypermotility. Biochemical studies in rat brain structures showed that 3-MT behaved as an antagonist of the noradrenergic system, i.e. accelerated noradrenaline metabolism and counteracted the inhibitory effect of amphetamine on the rate of noradrenaline metabolism. In contrast to a general view about the lack of physiological role of monoamine metabolites, these results for the first time strongly suggest that an extraneuronal metabolite of dopamine, 3-MT plays an important physiological role as an inhibitory regulator counteracting excessive stimulation of catecholaminergic neurons in the striatum. (C) 2008 Elsevier B.V. All rights reserved.