Catechol-O-methyltransferase (COMT) in rat brain: immunoelectron microscopic study with an antiserum against rat recombinant COMT protein

Karhunen, Tuula; Tilgmann, Carola; Ulmanen, Ismo; Panul, Pertti

doi:10.1016/0304-3940(95)11337-v

Cited by 66 publications

(41 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cellular localization of COMT in the brain is still poorly characterized. Based on a few immunohistochemical studies (Kaplan et al, 1981;Karhunen et al, 1995) and studies assaying COMT activity (Silberstein et al, 1972;Garbarg et al, 1975;Hansson and Sellström, 1983;Spatz et al, 1986), COMT appears to be located in both glia and neurons. Previous COMT mRNA distribution studies suggest neuronal rather than glial localization in rats and humans (Matsumoto et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Site-Specific Role of Catechol-O-Methyltransferase in Dopamine Overflow within Prefrontal Cortex and Dorsal Striatum

Yavich¹,

Forsberg²,

Karayiorgou³

et al. 2007

J. Neurosci.

244

205

View full text Add to dashboard Cite

Accumulating evidence from clinical and preclinical studies shows that catechol-O-methyltransferase (COMT) plays a significant role in dopamine metabolism in the prefrontal cortex, but not in the striatum. However, to what extent dopamine overflow in the prefrontal cortex and striatum is controlled by enzymatic degradation versus reuptake is unknown. We used COMT deficient mice to investigate the role of COMT in these two brain regions with in vivo voltammetry. A real-time analysis of evoked dopamine overflow showed that removal of dopamine was twofold slower in the prefrontal cortex of mice lacking COMT than in wild-type mice, indicating that half of the dopamine decline in this brain region results from COMT-mediated enzymatic degradation. Lack of COMT did not influence dopamine overflow/decline in the dorsal striatum. COMT-deficient mice demonstrated a small (20 -25%) but consistent increase in evoked dopamine release in the prefrontal cortex, but not in the dorsal striatum. Cocaine affected equally dopaminergic neurotransmission in the prefrontal cortex in both genotypes by prolonging 3-4 times dopamine elimination from extracellular space. Paradoxically, this happened without increase of the peak levels of evoked dopamine release. The present findings represent the first demonstration of the significant contribution of COMT in modulating the dynamics of dopamine overflow in the prefrontal cortex and underscore the therapeutic potential of manipulating COMT activity to alter dopaminergic neurotransmission in the prefrontal cortex.

show abstract

Section: Discussionmentioning

confidence: 99%

Site-Specific Role of Catechol-O-Methyltransferase in Dopamine Overflow within Prefrontal Cortex and Dorsal Striatum

Yavich¹,

Forsberg²,

Karayiorgou³

et al. 2007

J. Neurosci.

244

205

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

“…Due the extraneuronal location in the brain (astrocytes, capillary walls, and postsynaptic dendritic spines; Karhunen et al, 1995), the significance of catechol-O-methyltransferase (COMT) on dopamine metabolism remains secondary under normal conditions. Inhibition of COMT activity in rodents either via pharmacological intervention or via disruption of the Comt gene (Gogos et al, 1998) reveals only minor changes in their locomotor behavior and brain dopamine and noradrenaline levels in normal conditions (Gogos et al, 1998;Huotari et al, 2002).…”

mentioning

confidence: 99%

Effect of Dopamine Uptake Inhibition on Brain Catecholamine Levels and Locomotion in Catechol-O-methyltransferase-Disrupted Mice

Huotari

Sántha

Lucas

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Two different uptake processes terminate the synaptic action of released catecholamines in brain: the high-affinity uptake to presynaptic nerve terminals (uptake 1 , followed by oxidation by monoamine oxidase, MAO) or glial cells uptake (uptake 2 , followed by O-methylation by catechol-O-methyltransferase, COMT, and/or oxidation by MAO). For dopaminergic neurons, uptake by the high-affinity dopamine transporter (DAT) is the most effective mechanism, and the contribution of glial COMT remains secondary under normal conditions. In the present study we have characterized the role of COMT using COMT-deficient mice in conditions where DAT is inhibited by 1-[2-[bis(4-fluorophenyl)methoxy-]ethyl]-4-(3-phenylpropyl)-piperazine (GBR 12909) or cocaine. In mice lacking COMT, GBR 12909 results in total brain tissue dopamine levels generally higher than in wildtype mice but no such potentiation was ever seen in striatal extracellular fluid. Dopamine accumulation in nerve endings is more evident in striatum and hypothalamus than in cortex. Both GBR 12909 and cocaine induced hyperlocomotion in mice lacking COMT. Unexpectedly, hyperactivity induced by 20 mg/kg GBR 12909 was attenuated only in male COMT knockout mice, i.e., they had an inability to sustain the hyperactivity induced by DAT inhibition. Furthermore, attenuation of hyperlocomotion was observed also after cocaine treatment in both C57BL/6 (at 5 and 15 mg/kg) and 129/Sv (at 30 mg/kg) genetic background COMT-deficient male mice. Despite the possible interaction between DAT and extraneuronal uptake (and subsequently COMT), the role of COMT in dopamine elimination is still minimal in conditions when DAT is inhibited.The dopamine transporter (DAT) and monoamine oxidase (MAO) play key roles in dopamine elimination and are expected to have pleiotropic effects on susceptibility to a wide range of behavioral/psychiatric disorders and symptoms associated with dysregulation of dopamine transmission. Due the extraneuronal location in the brain (astrocytes, capillary walls, and postsynaptic dendritic spines; Karhunen et al., 1995), the significance of catechol-O-methyltransferase (COMT) on dopamine metabolism remains secondary under normal conditions.

show abstract

“…4 The role of COMT may be relatively more important in the prefrontal cortex since the more effective solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (SLC6A3) is scarce there. 5 COMT resides within both neurons and glial cells in the brain, 6,7 but in the prefrontal cortex and striatum most COMT mRNAs are found in neurons in humans and mice. 7,8 There are two major forms of COMT, a soluble shorter form (S-COMT) found in the cytoplasm and a longer membrane-bound form (MB-COMT) found on the cytoplasmic side of the rough endoplasmic reticulum, [9][10][11][12] with the latter being the predominant form, B70% of total COMT protein, expressed in the brain.…”

mentioning

confidence: 99%

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

et al. 2004

View full text Add to dashboard Cite

Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val 108/158 Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P ¼ 0.051) in ARVCF, and a stronger signal (global P ¼ 0.0019-0.0036) from three-marker haplotypes spanning the 3 0 portions of COMT and ARVCF, including Val 108/158 Met with Val 108/158 being the overtransmitted allele, consistent with previous studies. We also find Val 108/158 Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence. Molecular Psychiatry (2005) 10, 353-365.

show abstract

Catechol-O-methyltransferase (COMT) in rat brain: immunoelectron microscopic study with an antiserum against rat recombinant COMT protein

Cited by 66 publications

References 23 publications

Site-Specific Role of Catechol-O-Methyltransferase in Dopamine Overflow within Prefrontal Cortex and Dorsal Striatum

Site-Specific Role of Catechol-O-Methyltransferase in Dopamine Overflow within Prefrontal Cortex and Dorsal Striatum

Effect of Dopamine Uptake Inhibition on Brain Catecholamine Levels and Locomotion in Catechol-O-methyltransferase-Disrupted Mice

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

Contact Info

Product

Resources

About