Presynaptic regulation of extracellular dopamine levels in the medial prefrontal cortex and striatum during tyrosine depletion.
BACKGROUND
Available neurochemical probes that lower brain dopamine (DA) levels in man are limited by their tolerability and efficacy. For instance, the acute lowering of brain tyrosine is well tolerated, but only modestly lowers brain DA levels. Modification of tyrosine depletion to robustly lower DA levels would provide a superior research probe.


OBJECTIVE
The objective of this study was to determine whether the subthreshold stimulation of presynaptic DA receptors would potentiate tyrosine depletion-induced effects on extracellular DA levels in the medial prefrontal cortex (MPFC) and striatum of the rat.


METHODS
We administered quinpirole, a predominantly DA type 2 (D2R) receptor agonist, into the MPFC and striatum by reverse dialysis. A tyrosine- and phenylalanine-free neutral amino acid mixture [NAA(-)] IP was used to lower brain tyrosine levels. DA levels in the microdialysate were measured by HPLC with electrochemical detection.


RESULTS
Quinpirole dose-dependently lowered DA levels in MPFC as well as in the striatum. NAA(-) alone transiently lowered DA levels (80 % baseline) in the striatum, but had no effect in MPFC. The co-administration of NAA(-) and a subthreshold concentration of quinpirole (6.25 nM) lowered DA levels (50 % baseline) in both the MPFC and striatum. This effect was blocked by the mixed D2R/D3R antagonist haloperidol at IP doses that on their own did not affect DA levels (10.0 nmol/kg in the MPFC and 0.10 nmol/kg in the striatum).


CONCLUSIONS
Pharmacological stimulation of inhibitory D2R receptors during tyrosine depletion markedly lowers the extracellular DA levels in the MPFC and striatum. The data suggest that combining tyrosine depletion with a low dose of a DA agonist should robustly lower brain regional DA levels in man.
Louis Stokes Cleveland DVAMC, Research Service, 151W 10701 East Blvd, Cleveland, OH 44106, USA.
Zachary
Z
Brodnik
Manda
M
Double
George E
GE
Jaskiw
D000596:Amino Acids / Q000008:administration & dosage; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000378:metabolism; D019257:Quinpirole / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000172:deficiency*
D000596:Amino Acids; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D014443:Tyrosine; D006220:Haloperidol; D004298:Dopamine