The dopamine metabolite 3-methoxytyramine is a neuromodulator.
Dopamine (3-hydroxytyramine) is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT), can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1). Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3-MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine. In normal mice, the central administration of 3-MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, signaling events generally related to PKA-mediated cAMP accumulation. In mice lacking TAAR1, both behavioral and signaling effects of 3-MT were partially attenuated, consistent with the ability of 3-MT to activate TAAR1 receptors and cause cAMP accumulation as well as ERK and CREB phosphorylation in cellular assays. Thus, 3-MT is not just an inactive metabolite of DA, but a novel neuromodulator that in certain situations may be involved in movement control. Further characterization of the physiological functions mediated by 3-MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission, such as Parkinson's disease, dyskinesia and schizophrenia.
Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy.
Tatyana D
TD
Sotnikova
Jean-Martin
JM
Beaulieu
Stefano
S
Espinoza
Bernard
B
Masri
Xiaodong
X
Zhang
Ali
A
Salahpour
Larry S
LS
Barak
Marc G
MG
Caron
Raul R
RR
Gainetdinov
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D048049:Extracellular Signal-Regulated MAP Kinases; C001746:3-methoxytyramine; D004298:Dopamine