In vivo electrochemical studies of dopamine clearance in the rat substantia nigra: effects of locally applied uptake inhibitors and unilateral 6-hydroxydopamine lesions.
High-speed chronoamperometric recordings were used to measure the uptake and clearance of locally applied dopamine (DA) within the substantia nigra (SN) of anesthetized rats. To establish that DA clearance within the SN was mediated primarily by the DA transporter (DAT) rather than the norepinephrine transporter (NET) or the serotonin transporter (SERT), we locally applied uptake inhibitors with different selectivity profiles for the various amine transporters. Nomifensine, a DAT/NET inhibitor, significantly potentiated both the amplitude and the time course of the DA signals. In contrast, neither the selective NET inhibitor desipramine, nor the selective SERT inhibitor citalopram affected the DA signal, suggesting that NET and SERT do not contribute to DA uptake and clearance within the regions of the SN studied over the concentration ranges (1-5 microM) used. In unilaterally 6-hydroxydopamine-lesioned rats, the time course of the DA signal was increased in both the lesioned SN and striatum, relative to the unlesioned hemisphere, indicating loss of DAT and decreased DA uptake and clearance. In addition, when identical amounts of DA were injected in the striatum and SN, peak signal amplitudes were larger in the SN, suggesting that the amplitudes are related to the number of DAT sites in a given region of brain tissue. For signals of equivalent amplitudes, clearance rates were lower in the SN than in the striatum, consistent with a lower capacity for DAT-mediated DA uptake within the SN. These results suggest that the DAT is the major transporter responsible for DA clearance within the rat SN.
Hoffman
A F
AF
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Gerhardt
G A
GA
D000287:Administration, Topical; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000493:pharmacokinetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004563:Electrochemistry / Q000379:methods; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493216:Slc6a3 protein, rat; D016627:Oxidopamine; D004298:Dopamine