REGULATION OF EXTRACELLULAR DOPAMINE BY THE NOREPINEPHRINE TRANSPORTER

There is growing evidence of an interaction between dopamine and norep inephrine, To test the hypothesis that norepinephrine terminals are in volved in the uptake and removal of dopamine from the extracellular sp ace, the norepinephrine uptake blocker desmethylimipramine (DMI) was i nfused locally while the extracellular concentrations of dopamine were simultaneously monitored. DMI increased the extracellular concentrati ons of dopamine in the medial prefrontal cortex and nucleus accumbens shell but had no effect in the striatum. The combined systemic adminis tration of haloperidol and the local infusion of DMI produced an augme nted increase in extracellular dopamine in the cortex compared with th e increase produced by either drug alone. This synergistic increase in dopamine overflow is likely due to the combination of impulse-mediate d dopamine release produced by haloperidol and blockade of the norepin ephrine transporter. No such synergistic effects were observed in the nucleus accumbens and striatum. Local perfusion of the alpha(2)-antago nist idazoxan also increased the extracellular concentrations of dopam ine in the cortex. Although the stimulation of extracellular dopamine by idazoxan and DMI could be due to the increased extracellular concen trations of norepinephrine produced by these drugs, an increase in dop amine also was observed in lesioned rats that were depleted of norepin ephrine and challenged with haloperidol. This contrasted with the lack of an effect of haloperidol on cortical dopamine in unlesioned contro ls. These results suggest that norepinephrine terminals regulate extra cellular dopamine concentrations in the medial prefrontal cortex and t o a lesser extent in the nucleus accumbens shell through the uptake of dopamine by the norepinephrine transporter.