Brain catecholamine metabolism in catechol‐O‐methyltransferase (COMT)‐deficient mice

Abstract

Catechol-O-methyltransferase (COMT) catalyses the O-methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites. By means of homologous recombination in embryonic stem cells, a strain of mice has been produced in which the gene encoding the COMT enzyme is disrupted. We report here the levels of catecholamines and their metabolites in striatal extracellular fluid in these mice as well as in homogenates from different parts of the brain, under normal conditions and after acute levodopa administration. In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal. Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites. This finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase-dependent metabolism in terminating the actions of catecholamines at nerve terminals. In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations. Notably, in some cases these changes appear to be Comt gene dosage-dependent, brain-region specific and sexually dimorphic. Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes.

COMT Polymorphisms and Anxiety-Related Personality Traits

“…Furthermore, several studies have found associations of val158met and panic disorder specific to women (Domschke et al, 2004;Woo et al, 2004). These results also fit well with the fact that most anxiety (and depressive) disorders are more common in women, and are consistent with preclinical data indicating the possibility for sexually dimorphic effects of COMT variants on catecholamine metabolism (Huotari et al, 2002). This observation must be interpreted with caution, however, because there were more than twice as many women as men in our sample, so we might have lacked power to detect a signal in men.…”

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow

“…However, animal studies indicate that COMT plays only a minimal role in the clearance of synaptic dopamine, even under conditions of low dopamine transporter activity. [45][46][47] Furthermore, COMT genotype appears to account for only a small amount (2-4%) of shared variance with WCST performance. 52,105 Thus, this small effect of COMT genotype on cognitive performance may be especially difficult to detect in younger and more heterogeneous sample of schizophrenia patients.…”

“…29,[39][40][41][42][43] Elimination of extracellular dopamine relies on synaptic reuptake (via dopamine transporter and norepinephrine transporter) as well degradation by monoamine oxidase and catechol-O-methyl transferase (COMT). [44][45][46][47] Owing to its role in the catabolism of dopamine, the COMT gene has been extensively studied as a schizophrenia candidate gene. In humans, there is a common V 158 M functional polymorphism 48 where a methionine (Met) substituted for a valine (Val) leads to a four-fold reduction in COMT enzyme activity.…”

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

“…Previous experimental data indicate that COMT is especially relevant in modulating prefrontal cortical dopamine neurotransmission. First, studies of COMT knockout mice have demonstrated that dopamine levels are increased in the prefrontal cortex of these mice under varying conditions, but not in the striatum (Gogos et al, 1998;Huotari et al, 2002). Pharmacological studies in rats have also shown that the catabolic flux of synaptic dopamine through the COMT pathway is much greater in the prefrontal cortex as compared to the striatum (Karoum et al, 1994).…”