Dopamine in the hippocampus is cleared by the norepinephrine transporter

Abnormal dopaminergic neurotransmission in the hippocampus may be involved in certain aspects of cognitive dysfunction. In the hippocampus, there is little, if any, expression of dopamine transporters (DAT), indicating that the mechanism for dopamine clearance differs from that in the striatum. Here, by means of in-vivo microdialysis in freely moving rats, we tested the hypothesis that the norepinephrine transporter (NET) is involved in dopamine clearance in the hippocampus. We found that systemic administration of the selective NET inhibitor reboxetine (3 mg/kg) and the psychostimulants amphetamine (0.5 mg/kg) and cocaine (10 mg/kg) increased hippocampal dopamine efflux. Local administration of reboxetine (300 μM) produced a large increase in hippocampal dopamine levels that could not be further enhanced by the addition of the NET/DAT inhibitor nomifensine (100 μM). Administration of the specific DAT inhibitor GBR12909 at a concentration (1 mM) that robustly increased dopamine in the nucleus accumbens had a comparably smaller effect in the hippocampus. In line with a minor role of DAT in the hippocampus, we detected very little DAT in this area using ligand binding with radiolabelled RTI-55. Moreover, in contrast to raclopride (100 μM), a dopamine D2-autoreceptor antagonist, local administration of the α2-adrenoceptor antagonist idazoxan (100 μM) increased hippocampal dopamine. Taken together, our data demonstrate an interaction between dopamine and norepinephrine systems in the hippocampus. It is proposed that this interaction originates from a shared uptake mechanism at the NET level.