title: Dopamine in the hippocampus is cleared by the norepinephrine transporter.
abstract: 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.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. aborgkvist@yahoo.se
authors.forename: Anders
authors.initials: A
authors.lastname: Borgkvist
authors.forename: Torun
authors.initials: T
authors.lastname: Malmlöf
authors.forename: Kristin
authors.initials: K
authors.lastname: Feltmann
authors.forename: Maria
authors.initials: M
authors.lastname: Lindskog
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004333:Drug Administration Routes; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D019329:Idazoxan / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009025:Morpholines / Q000494:pharmacology; D009627:Nomifensine / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000502:physiology*; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077593:Reboxetine; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014851:Wakefulness
chemical_list: D018759:Adrenergic Uptake Inhibitors; D058669:Adrenergic alpha-2 Receptor Antagonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D026941:Sodium Channel Blockers; D009627:Nomifensine; D020891:Raclopride; D013779:Tetrodotoxin; D000077593:Reboxetine; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine; D019329:Idazoxan