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Distribution, regulation and physiological roles of catechol-O-methyltransferase (COMT) in rodents

Year: 2012
Type: dissertation
Abstract: Catechol-O-methyltransferase (COMT) metabolises catecholamines such as dopamine, noradrenaline and adrenaline, which are well-characterised neurotransmitters that play important roles in the regulation of physiological processes. The COMT enzyme exists in membrane-bound (MB-COMT) and soluble (S-COMT) forms that are both encoded by the same gene. Presently, the necessity and physiological importance of the existence of two COMT isoenzymes remains partially unknown. The aim of this thesis was to provide new insights into the specific distribution patterns of MB-COMT and S-COMT, to verify the proposed hormonal regulation of COMT and to investigate its possible physiological role in feeding behaviour. We used two different study designs to address the distribution of COMT in the brain. First, we utilised dopaminergic and noradrenergic toxins to assess the presence of COMT in presynaptic neurons originating from selected brain areas. Successful lesioning of the neurons was confirmed by measuring dopamine and noradrenaline levels in their respective projection areas. However, despite successful lesioning, no changes in COMT protein expression or activity could be noted, indicating that COMT is not present in presynaptic dopaminergic and noradrenergic neurons. The specific distribution patterns of MB-COMT and S-COMT were studied in an S-COMT-deficient mouse line (lacking the S-COMT form of COMT). By comparing these mice to wild type mice, we found that the general distribution patterns of both COMT isoforms were similar between the genotypes. Notably, S-COMT-deficient mice did not exhibit nuclear COMT staining, indicating that MB-COMT is not present in cell nuclei. Furthermore, S-COMT-deficient mice allowed us to examine the association of MB-COMT with the plasma membrane. Contrary to previous assumptions, MB-COMT is not associated with the plasma membrane, but instead may be attached to intracellular cytosolic membranes. The proposed regulatory function of oestrogens on COMT activity was studied by subjecting male and female Wistar rats to different hormonal treatments over a two-week period. Antagonising/modulating the effects of oestrogen via the administration of tamoxifen increased COMT activity and expression. Unexpectedly, increasing oestradiol levels in male rats also led to the upregulation of COMT expression in several tissues, underscoring the importance of COMT in the clearance of biologically active oestrogen metabolites. Finally, we used female rodents (rats and mice) to address the possible role of COMT in feeding behaviour. Our studies revealed that acute COMT inhibition affects the feeding pattern of rodents; COMT-inhibited animals have significantly more ''long'' meals (lasting 300 sec or more) than vehicle-treated animals. Notably, a relatively short starvation period of 16 h induced a slight, albeit not significant, decrease in prefrontal and striatal COMT activity in mice. This finding is interesting, especially as COMT activity is thought to be rather robust, and may suggest the increased importance of COMT during altered physiological status. In conclusion, although the specific roles of MB-COMT and S-COMT remain partly obscure, their absence from presynaptic dopaminergic and noradrenergic neuron terminals suggests a secondary (and perhaps more modulatory) role of COMT in neurotransmitter metabolism in the brain. Furthermore, the observed decrease in COMT activity after a relatively short starvation period suggests that COMT has an increased importance during certain physiological states. Finally, the observed regulatory function of oestrogens on COMT activity and protein expression in vivo may be of clinical importance as COMT inhibitors are used as adjuncts in the treatment of PD.
Language: English
Open Access status: green
OpenAlex ID: W1591713592
Cites: 189
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Related to: 10