title: Elimination of extracellular dopamine in the medial prefrontal cortex of conscious mice analysed using selective enzyme and uptake inhibitors.
abstract: We have shown in a previous study that in the medial prefrontal cortex (mPFC) of Comt knockout animals, uptake1 followed by oxidation accounts for approximately 50% and uptake2 followed by O-methylation for the remaining 50% of dopamine clearance. However, compensatory mechanisms in genetically modified animals may have affected the result. Therefore, in the present study, we gave a high dose (30 mg/kg) of tolcapone in combination with pargyline and reboxetine to C57BL/6J mice to see whether the earlier findings could be confirmed. The three drugs were also given together. We used intracerebral microdialysis to determine the levels of extracellular dopamine and its metabolites in the mPFC. In addition, we analyzed dopamine, 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) contents in cortical and striatal synaptosomes to estimate the amount of releasable dopamine and dopamine turnover. In the prefrontal cortex of male C57BL/6J mice, the combination of two drugs (pargyline + tolcapone or reboxetine + tolcapone) generally elevated extracellular dopamine levels more than any single drug. Similar responses, although much weaker, were observed in female mice. Unexpectedly, triple treatment with pargyline, reboxetine and tolcapone did not increase dopamine outflow in the mPFC in either sex, and the treatment actually diminished dopamine outflow in the dorsal striatum. This seems to indicate that such an extensive treatment induces a fast and effective shut-down of dopamine release both in the mPFC and striatum to protect the brain from excess dopaminergic stimulation. The observed decrease in extracellular dopamine levels was not due to the depletion of releasable dopamine because abundant amounts of dopamine were present in synaptosomes. These results imply that the relative proportion of COMT-induced dopamine clearance may be somewhat lower than earlier estimated.
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland. anne.tammimaki@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Tammimaki
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland.|Division of Pharmacology and Toxicology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Estonia.
authors.forename: A
authors.initials: A
authors.lastname: Aonurm-Helm
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Kaenmaki
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland.
authors.forename: P T
authors.initials: PT
authors.lastname: Mannisto
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000235:genetics; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D000077593:Reboxetine; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000077867:Tolcapone
chemical_list: D018759:Adrenergic Uptake Inhibitors; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009025:Morpholines; D009596:Nitrophenols; D015102:3,4-Dihydroxyphenylacetic Acid; D000077593:Reboxetine; D010293:Pargyline; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase; D004298:Dopamine; D006719:Homovanillic Acid