Transport of dopamine at the blood-brain barrier of the guinea pig: inhibition by psychotropic drugs and nicotine.
OBJECTIVE
Transport of dopamine (DA) across the blood-brain barrier (BBB) was examined in guinea pigs.


METHODS
In situ brain perfusion (1-10 min), capillary depletion, and high pressure liquid chromatography (HPLC) were used.


RESULTS
There was a saturable DA influx into the brain with a KM of 389 +/- 55 nM, and a VMAX of 1.95 +/- 0.25 pmol/min/g of brain. The diffusion constant, KD, was not significantly different from zero. About 0.5% of DA remained tightly bound to cerebral microvessels isolated from the perfused brain. DA influx into the brain was not altered by the monoamine oxidase-B (MAO-B) inhibitor pargyline (50 microM). HPLC analysis of perfused brain confirmed transport of intact DA, and no detectable increases in DA metabolites were observed. At perfusate concentrations of 500 nM, several dopaminergic receptor antagonists inhibited [3H]-DA (21 nM) influx; the percent inhibitions for the mixed D1 and D2 antagonists haloperidol and chlorpromazine, the D1 antagonist SCH-23390, and the D2 antagonist spiperone were 90%, 68%, 77%, and 50%, respectively. Brain perfusion with nicotine (500 nM) inhibited DA uptake by 86%. This nicotine effect was not altered by mecamylamine, but was partially prevented by the nicotinic receptor antagonist hexamethonium.


CONCLUSIONS
(a) A significant cerebrovascular permeability to intact DA is mediated by a MAO-B independent specific transport system at the BBB, (b) this system could be inhibited by D1 and D2 DA receptor antagonists, and (c) DA blood-to-brain transport was inhibited by nicotine.
Martel
C L
CL
Department of Neurosurgery, University of Southern California School of Medicine, Los Angeles 90033, USA.
Mackic
J B
JB
Adams
J D
JD
McComb
J G
JG
Weiss
M H
MH
Zlokovic
B V
BV
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism / Q000493:pharmacokinetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009538:Nicotine / Q000494:pharmacology*; D010293:Pargyline / Q000494:pharmacology; D010477:Perfusion; D011619:Psychotropic Drugs / Q000494:pharmacology*; D013395:Sucrose; D014316:Tritium
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D011619:Psychotropic Drugs; D014316:Tritium; D013395:Sucrose; D009538:Nicotine; D010293:Pargyline; D004298:Dopamine