Heterologous monoamine reuptake: lack of transmitter specificity of neuron-specific carriers

The effect of systemic administration of desmethylimipramine (DMI), an inhibitor of the noradrenaline (NA) reuptake carrier, and of GBR 12909, an inhibitor of the dopamine (DA) reuptake carrier, on the in vivo extracellular concentrations of dopamine (DA) was studied by transcerebral dialysis in the prefrontal cortex and in the dorsal caudate of freely moving rats. In the NA-rich prefrontal cortex only DMI increased extracellular DA concentrations whereas in the dorsal caudate only GBR 12909 was effective. Haloperidol increased extracellular DA concentrations more effectively in the dorsal caudate than in the prefrontal cortex. Pretreatment with DMI, which failed to modify the effect of haloperidol in the dorsal caudate, potentiated its action in the prefrontal cortex. The reverse was obtained after GBR 12909+ haloperidol in the two areas. 6-hydroxydopamine lesioning of the dorsal NA bundle prevented the ability of DMI to increase DA concentrations. The results suggest that reuptake into NA terminals is an important mechanism by which DA is cleared from the extracellular space in a NA-rich area such as the prefrontal cortex. The elevated extracellular concentrations of DA resulting from blockade of such mechanism by tricyclic antidepressants may play a role in the therapeutic effects of these drugs.