Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition.
In vitro rotating disk electrode (RDE) voltammetry and in vivo microdialysis were used to characterize dopamine clearance in the rat medial prefrontal cortex (mPFC). RDE studies indicate that inhibition by cocaine, specific inhibitors of the dopamine transporter (DAT) and norepinephrine transporter (NET), and low Na(+) produced a 50-70% decrease in the velocity of dopamine clearance. Addition of the monoamine (MAO) inhibitors, l-deprenyl, clorgyline, pargyline, or in vivo nialamide produced 30-50% inhibition. Combined effects of uptake inhibitors with l-deprenyl on dopamine clearance were additive (up to 99% inhibition), suggesting that at least two mechanisms may contribute to dopamine clearance. Dopamine measured extracellularly 5 min after exogenous dopamine addition to incubation mixtures revealed that most conditions of DAT/NET inhibition did not produce elevated dopamine levels above controls. Inhibition of MAO produced elevated dopamine levels only after long-term, but not short-term, incubation in vitro. Short-term incubation of l-deprenyl combined with DAT and NET uptake inhibitors increased dopamine above control levels, consistent with more than one mechanism of dopamine clearance. Local infusion of pargyline (100 or 300 microm) into the mPFC or striatum via microdialysis produced more pronounced and immediate increases in mPFC dopamine levels compared with striatum. Furthermore, dopamine elevation in the mPFC was not accompanied by a decrease in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, as found in the striatum. These findings may have revealed a unique mechanism of mPFC dopamine clearance and therefore contribute to the understanding of multiple behaviors that involve mPFC dopamine transmission, such as schizophrenia, drug abuse, and working memory function.
Wayment
H K
HK
Department of Chemistry, Washington State University, Pullman, Washington 99164, USA.
Schenk
J O
JO
Sorg
B A
BA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004563:Electrochemistry / Q000295:instrumentation; D004567:Electrodes, Implanted; D005110:Extracellular Space / Q000378:metabolism*; D006719:Homovanillic Acid / Q000032:analysis / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D017551:Microdialysis; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010293:Pargyline / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D027981:Symporters
D015306:Biogenic Monoamines; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; D027981:Symporters; D015102:3,4-Dihydroxyphenylacetic Acid; D010293:Pargyline; D012964:Sodium; D008995:Monoamine Oxidase; D003042:Cocaine; D004298:Dopamine; D006719:Homovanillic Acid