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 microdialysi s were used to characterize dopamine clearance in the rat medial prefrontal cortex (mPFC). RDE studies indicate that inhibition by cocaine, specific i nhibitors of the dopamine transporter (DAT) and norepinephrine transporter (NET), and low Na+ produced a 50-70% decrease in the velocity of dopamine c learance. Addition of the monoamine (MAO) inhibitors, L-deprenyl, clorgylin e, pargyline, or in vivo nialamide produced 30-50% inhibition. Combined eff ects of uptake inhibitors with L-deprenyl on dopamine clearance were additi ve (up to 99% inhibition), suggesting that at least two mechanisms may cont ribute to dopamine clearance. Dopamine measured extracellularly 5 min after exogenous dopamine addition to incubation mixtures revealed that most cond itions of DAT/NET inhibition did not produce elevated dopamine levels above controls. Inhibition of MAO produced elevated dopamine levels only after l ong-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 c learance. Local infusion of pargyline (100 or 300 muM) into the mPFC or str iatum via microdialysis produced more pronounced and immediate increases in mPFC dopamine levels compared with striatum. Furthermore, dopamine elevati on in the mPFC was not accompanied by a decrease in the dopamine metabolite s, 3,4-dihydroxyphenylacetic acid and homovanillic acid, as found in the st riatum. These findings may have revealed a unique mechanism of mPFC dopamin e clearance and therefore contribute to the understanding of multiple behav iors that involve mPFC dopamine transmission, such as schizophrenia, drug a buse, and working memory function.