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 α1 and striatal dopamine D1 and D2 receptors in nanomolar concentration range, and to cortical α2 adrenoceptor at low micromolar concentration. Bilateral intrastriatal injections of 3-MT (0.25 µmol in 0.5 µl) 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.