Abstract
The catechol-O-methyltransferase (COMT) enzyme metabolises catecholamines. COMT inhibitors are licensed for the adjunctive treatment of Parkinson's disease and are attractive therapeutic candidates for other neuropsychiatric conditions. COMT regulates dopamine levels in the prefrontal cortex (PFC) but plays a lesser role in the striatum. However, its significance in other brain regions is largely unknown, despite its links with a broad range of behavioural phenotypes hinting at more widespread effects. Here, we investigated the effect of acute systemic administration of the brain-penetrant COMT inhibitor tolcapone on tissue levels of dopamine, noradrenaline, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). We examined PFC, striatum, hippocampus and cerebellum in the rat. We studied both males and females, given sexual dimorphisms in several aspects of COMT's function. Compared with vehicle, tolcapone significantly increased dopamine levels in the ventral hippocampus, but did not affect dopamine in other regions, nor noradrenaline in any region investigated. Tolcapone increased DOPAC and/or decreased HVA in all brain regions studied. Notably, several of the changes in DOPAC and HVA, particularly those in PFC, were more prominent in females than males. These data demonstrate that COMT alters ventral hippocampal dopamine levels, as well as regulating dopamine metabolism in all brain regions studied. They demonstrate that COMT is of significance beyond the PFC, consistent with its links with a broad range of behavioural phenotypes. Furthermore, they suggest that the impact of tolcapone may be greater in females than males, a finding which may be of clinical significance in terms of the efficacy and dosing of COMT inhibitors.
Highlights
Catechol-O-methyltransferase (COMT) metabolises catecholcontaining compounds, including dopamine [1,2,3,4]
The sex differences following tolcapone administration were large enough to result in main effects of sex on DOPAC levels (F’s.7.1; p’s,0.005; female DOPAC.male DOPAC) in the prefrontal cortex (PFC) and cerebellum
Taken together with the dopamine and DOPAC findings outlined above, these results indicate that COMT inhibition alters dopamine metabolism in all regions studied
Summary
Catechol-O-methyltransferase (COMT) metabolises catecholcontaining compounds, including dopamine [1,2,3,4]. Given the use of COMT inhibitors for Parkinson’s disease, the impact of tolcapone on dopamine levels has been well-studied in the striatum. In this region, COMT inhibition typically has little or no effect on dopamine levels, measured either in tissue homogenates or extracellularly [8,9,10]. COMT inhibition typically has little or no effect on dopamine levels, measured either in tissue homogenates or extracellularly [8,9,10] These data are in keeping with the lack of a change in striatal dopamine levels in the COMT null mouse [2,4,11,12]. COMT inhibition increases dopaminergic transmission in the prefrontal cortex (PFC) [1,3], consistent with findings of increased PFC dopamine levels in the COMT null mouse, compared with wild type littermates [2,4]
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