Dopamine reuptake by norepinephrine neurons: exception or rule?

Dopamine reuptake by norepinephrine terminals can occur in brain areas such as the prefrontal cortex, the nucleus accumbens shell, and the bed nucleus of stria terminalis that are innervated, although unevenly, by both dopamine and norepinephrine neurons. Therefore the antidepressants that bind selectively the norepinephrine transporter might produce their therapeutic effect by raising the extracellular concentration of dopamine besides that of norepinephrine. Moreover, cocaine can be reinforcing even in knock-out mice for the dopamine transporter because it might raise synaptic dopamine in the nucleus accumbens shell by preventing its uptake by the norepinephrine transporter, an effect that could take place even in wild animals. Recently, it has also been suggested that dopamine can be co-released with norepinephrine by norepinephrine neurons, although it is not clear whether this feature might be related to a previous nonspecific uptake of dopamine by the norepinephrine transporter. In this review we discuss the potential role of the nonspecific uptake of dopamine by norepinephrine transporter in the mechanism of action of drugs of abuse, antipsychotics, and antidepressants.