Immunohistochemical study of catechol-O-methyltransferase in the human mesostriatal system

Kästner, Anne; Anglade, Philippe; Bounaix, C.; Damier, Philippe; Javoy‐Agid, F.; Bromet, Norbert; Agid, Yves; Hirsch, Étienne C.

doi:10.1016/0306-4522(94)90379-4

Cited by 52 publications

(24 citation statements)

References 42 publications

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“…180 The longer transcript can give rise to MB-and S-COMT, whereas only S-COMT is produced from the shorter transcript; the latter is rare in human brain. 180,182,183 Early studies suggested that COMT, especially S-COMT, was a glial enzyme, but subsequent analyses show that COMT is expressed primarily in neurons, and is much more abundant in prefrontal cortex and hippocampus than in striatum or in brainstem dopamine neurons, 178,183,184 supporting conclusions from pharmacological studies that COMT inactivates catechols at postsynaptic sites. 185 The distribution, together with other data, 186,187 implicates COMT in cortical interneuronal monoaminergic signalling, especially dopamine.…”

Section: Catechol-o-methyl Transferase (Comt)mentioning

confidence: 99%

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

2004

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This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications. Molecular Psychiatry (2005) 10, 40-68.

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Section: Catechol-o-methyl Transferase (Comt)mentioning

confidence: 99%

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

2004

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Section: Discussionmentioning

confidence: 99%

“…In the human striatum COMT immunoreactivity has been detected in both the cell bodies and dendritic spines of medium spiny neurons (MSNs), but not in the presynaptic terminals which contact MSN dendritic spines (Kastner et al 1994;Karhunen et al 1995). However, COMT has been localized to the cell bodies of melanized midbrain neurons (Kastner et al 1994). To determine whether the Comt transgene expression in the midbrain occurred in dopamine neurons, we performed a double fluorescence staining procedure using a riboprobe specific for the Comt transgene and an antibody selective for the dopamine cell marker tyrosine hydroxlyase (TH).…”

Section: Discussionmentioning

confidence: 99%

“…1B). Although CamKIIa expression is normally restricted to the forebrain, this unusual transgenic expression pattern is fortuitous because COMT has previously been localized to the cell bodies of melanized midbrain neurons (presumed to be dopamine neurons) in human tissue (Kastner et al 1994). To determine whether transgenic Comt was expressed in dopamine neurons, we combined in situ hybridization using a transgene specific probe with immunostaining using an anti-TH antibody.…”

Section: Generation Of a Transgenic Mouse Model Of Increased Comt Actmentioning

confidence: 99%

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Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum

et al. 2014

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A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val 158 allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans. Here we explore a novel transgenic mouse model of increased COMT activity, equivalent to the relative increase in activity observed with the human COMT Val 158 allele. By performing an extensive battery of behavioral tests, we found that COMT overexpressing mice (COMT-OE mice) exhibit cognitive deficits selectively in the domains that are affected by the COMT Val 158 allele, stimulus-response learning and working memory, functionally validating our model of increased COMT activity. Although we detected no changes in the level of markers for dopamine synthesis and dopamine transport, we found that COMT-OE mice display an increase in dopamine release capacity in the striatum. This result suggests that increased COMT activity may not only affect dopamine signaling by enhancing synaptic clearance in the cortex, but may also cause changes in presynaptic dopamine function in the striatum. These changes may underlie the behavioral deficits observed in the mice and might also play a role in the cognitive deficits and increased psychiatric disease risk associated with genetic variation in COMT activity in humans.The catechol-O-methyl transferase (COMT) enzyme degrades catecholamines, including dopamine. A single nucleotide polymorphism in the human COMT gene (Val 158 ) increases the thermostability of the enzyme-thereby increasing its level of activity compared to the 158

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“…Because the observed difference can not be attributed to a differential supply of L-DOPA to the brain, it is reasonable to conclude that central COMT inhibition, by reducing the rate of dopamine metabolism, contributes to the higher extracellular dopamine concentrations. Immunohistochemical studies demonstrated the presence of COMT in glial cells and in the cell bodies and spines of neurones that are postsynaptic to dopaminergic terminals (Kastner et al, 1994;Karhunen et al, 1995). Microdialysis studies showed that 3-MT, the COMT metabolite of dopamine, parallels the release of the neurotransmitter (Brown et al, 1991), suggesting that COMT plays a role in the metabolism of released dopamine.…”

Section: Discussionmentioning

confidence: 98%

The central catechol-O-methyltransferase inhibitor tolcapone increases striatal hydroxyl radical production in l-DOPA/carbidopa treated rats

et al. 2001

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Inhibition of catechol catechol-O-methyltransferase (COMT) in the brains of subjects treated with L-DOPA (L-3,4-dihydroxylphenylalanine) and an aromatic amino acid decarboxylase (AADC) inhibitor is suggested to cause an increase of L-DOPA, which might lead to oxidative damage through enhanced formation of free radicals. To investigate this hypothesis, the acute effects of two doses of the systemically administered COMT inhibitors entacapone (peripheral) and tolcapone (peripheral and central) on the extracellular formation of hydroxyl radicals in vivo following treatment with L-DOPA and the AADC inhibitor carbidopa were examined. The formation of extracellular hydroxyl radicals were determined by the measurement of 2,3-dihydroxybenzoic acid (2,3-DHBA), a reaction product of hydroxyl radicals with sodium salicylate, using microdialysis in the striatum of anesthetised rats. The COMT inhibitors were administered together with 50 mg/kg i.p. carbidopa as 5% gum arabic suspensions intraperitoneally (i.p.) at doses of 0, 1.0, and 10 mg/kg body weight to a total of 36 male HAN-Wistars rats. L-DOPA was injected i.p. 40 min after drugs of interest. Microdialysis samples were collected every 20 min for 400 min at a perfusion rate of 1 microl/min. Systemically administered 10 mg/kg tolcapone, but not entacapone, induced an increase in hydroxyl radical formation in the striatum of anesthetised rats following treatment with L-DOPA/carbidopa. The increase in hydroxyl radical formation was reflected by higher extracellular concentrations of the hydroxylate product of salicylate, 2,3-DHBA, peaking at 192% of baseline at the end of the observation period. Similar results were also found using the AUC (area under the curve) value estimated for the observation period. We conclude that the increase in hydroxyl radical formation is likely to result from an increased rate of monoamine oxidase-mediated and non-enzymatic (autoxidation) dopamine metabolism following increased central availability caused by reduction in COMT-mediated metabolism. We cannot, however, exclude the possibility that hydroxyl radicals are produced by tolcapone as a result of uncoupling mitochondrial oxidative phosphorylation.

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Immunohistochemical study of catechol-O-methyltransferase in the human mesostriatal system

Cited by 52 publications

References 42 publications

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum

The central catechol-O-methyltransferase inhibitor tolcapone increases striatal hydroxyl radical production in l-DOPA/carbidopa treated rats

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