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PubMed2004

Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum.

Recent studies provide evidence that anxiety disorders may be linked to malfunction of serotonin neurotransmission or impaired activity of enzymes metabolising the catecholamines. Functional polymorphisms in the MAO-A uVNTR promoter gene, the COMT gene (Val158Met) exon 4, and the 5-HTT promoter gene (44 bp ins/del) were investigated in 101 patients with phobic disorders of the anxiety spectrum and 202 controls matched to the patients for sex, age and ethnicity. There were no significant differences between controls and patients in the allele and genotype frequencies of the 5-HTT and COMT gene polymorphisms. The frequency of >3 repeat alleles of the MAO-A gene polymorphism was significantly higher in female patients suffering from anxiety disorders, specifically panic attacks and generalized anxiety disorder. There was also a trend for the more frequent presence of >3 repeat alleles in female patients with agoraphobia and specific phobia, in contrast to female patients with social phobia, who did not differ from controls. The results support a possible role of the MAO-A gene in anxiety disorders.

Adult↗
PubMed1998

Conditioned place preference induced by a combination of L-dopa and a COMT inhibitor, entacapone, in rats.

The interaction of dopamine (DA) precursor L-dopa and catechol-O-methyltransferase (COMT) inhibitor, entacapone, was examined in rats using conditioned place preference (CPP) paradigm to assess reinforcement, and by measuring DA metabolism in the striatum and the limbic forebrain. Neither L-dopa (100 mg/kg i.p.) nor entacapone (30 mg/kg i.p.) alone induced CPP, but in combination they induced significant CPP. Entacapone alone had no effect on limbic or striatal DA concentrations, while it reduced the concentrations of the COMT products 3-methoxytyramine (3-MT), a metabolite reflecting DA release, and homovanillic acid (HVA) in both brain areas. L-dopa elevated limbic but not striatal 3-MT. L-dopa also slightly elevated limbic DA but had no effect on striatal DA concentration. L-Dopa-induced increase of 3-MT was attenuated by entacapone. Our results show for the first time that L-dopa is able to produce CPP in intact animals. This effect may be related to the findings that L-dopa increases synaptic DA concentrations in the limbic areas, and entacapone may enhance this elevation as it prevents the synaptic metabolism of DA.

Animals↗
PubMed2001

Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats.

6-Nitronoradrenaline, a bioactive compound recently identified in the brain, is known to inhibit catechol-O-methyltransferase. To study its effect on dopamine metabolism, it was administered into rat striatum via a microdialysis probe. Other nitrated catechols (6-nitrodopamine, 6-nitro-DOPAC and 5-nitro-HVA) were studied for comparison. Tolcapone, a selective catechol-O-methyltransferase inhibitor, was used as a positive reference compound. Both 6-nitronoradrenaline and tolcapone increased striatal extracellular dopamine levels during the perfusion (at 100 microM concentration but not at 10 microM) and decreased the efflux of homovanillic acid. Tolcapone, but not other nitrated catechols, increased 3,4-dihydroxyphenylacetic acid efflux. None of the compounds inhibited MAO-B activity at 100 microM or lower. At 1 mM, 6-nitrodopamine inhibited MAO-B by 60%. Compared to tolcapone, other nitrated catechols were very weak COMT inhibitors in vitro. Neither tolcapone nor 6-nitronoradrenaline modified the metabolism of L-dopa which was given peripherally. In binding studies, both 6-nitronoradrenaline and other nitrocatechols failed to affect the dopamine transporter even at high micromolar concentrations. In conclusion, exogenous 6-nitronoradrenaline can act as a COMT inhibitor in the striatum and elevate striatal dopamine levels without inhibiting dopamine reuptake. Whether endogenous 6-nitronoradrenaline can be formed also in vivo in the striatum and act as a regulator of dopaminergic tone remains to be determined.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

An association study between 5-HTTLPR polymorphism, COMT polymorphism, and Tourette's syndrome.

Several lines of evidence suggest that a genetic component underlies Tourette's syndrome (TS). We investigated both the role of the insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and that of the Val-158-Met substitution in the catechol-O-methyl-transferase (COMT) gene in conferring susceptibility to TS. Fifty-two TS patients were recruited and compared with a control group of 63 healthy subjects. Neither a genotypic nor an allelic association was found; subdividing TS patients according to clinical variables, such as a co-diagnosis of obsessive-compulsive disorder (OCD) and a positive family history for obsessive compulsive disorder or tics, also failed to reveal a significant association. The lack of significance for 5-HTTLPR and COMT polymorphisms in conferring liability to TS does not exclude a role of different functional polymorphisms in genes coding for serotonergic or dopaminergic structures in the etiology of TS. In fact, TS is a complex disorder and these genes most likely have only a minor genetic effect in its etiology.

Adult↗
PubMed2000

Increased formation of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, in human breast cancer tissue and its relationship to GSTP1 and COMT genotypes.

Reactive oxygen species (ROS) induced damage to DNA plays a major role in carcinogenesis. In order to estimate the level of oxidative damage and its role in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined in DNA isolated from human breast tissue. Furthermore, we investigated whether polymorphisms in genes for enzymes involved in generation and elimination of ROS had any association with the level of 8-OHdG in breast tissue. In this study, the level of 8-OHdG in DNA was measured by the high performance liquid chromatography-electrochemical detector (HPLC-ECD) method. Genotypes of cytochrome P450 (CYP)1A1, glutathione S-transferase (GST)M 1, GSTP1 and catechol O-methyltransferase (COMT) were determined by PCR-based restriction fragment length polymorphism analysis. A total of 61 Japanese patients were included in the study. The mean level of 8-OHdG in DNA of breast cancer tissues was 2.07 +/- 0.95 per 10(5) dG residues, while the mean level of 8-OHdG in DNA of non-cancerous breast tissues was 1.34 +/- 0.46 per 10(5) dG residues. The 8-OHdG levels in DNA of breast cancer tissues were significantly higher than those of their corresponding non-cancerous breast tissues (P < 0.0001). There was negative correlation between the clinical stage and the mean level of 8-OHdG in DNA of breast cancer tissues. Furthermore, patients with genotype of high GSTP1 activity had lower level of 8-OHdG in DNA of breast cancer tissues than others. On the contrary, the mean level of 8-OHdG in DNA of breast cancer tissues was higher among patients with genotype of high COMT activity. Our findings support the assumption that cancer cells are more exposed to oxidative stress than adjacent non-cancerous tissue. Genetic polymorphisms in enzymes involved in ROS metabolism may have a role in individual susceptibility to oxidant-related breast disease. At the same time, reduction of oxidative stress is thought to be a very important measure for primary prevention of breast cancer.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

The increased utilisation of dopamine agonists and the introduction of COMT inhibitors have not reduced levodopa consumption--a nation-wide perspective in Sweden.

OBJECTIVE: To study the impact of the new pharmacological treatment strategies in Parkinson's disease by analysis of the sales of dopaminergic drugs in Sweden 1990-2001. METHODS: Invoice statistics and statistics on prescription sales of dopaminergic drugs 1990-2001 were obtained from the 906 public pharmacies and the 89 hospital pharmacies in Sweden. The Swedish Diagnosis and therapy survey was used to study the diagnosis the drugs were prescribed for. RESULTS: During the period the sales expressed in DDD/1000 inhabitants and day increased from 1.75 to 1.86 (6%) for levodopa and from 0.04 to 0.27 (575%) for dopamine agonists. The increase in sales of dopamine agonists occurred after 1997 and consisted entirely of the sales of the new agonists, cabergoline, pramipexole and ropinirole. In Swedish crowns the total sales of dopaminergic drugs increased with 126% during the period. The cost for the dopamine agonists was 8% of the total cost for dopaminergic drugs in 1990 and 23% in 2001. The prescription sales figures of levodopa and dopamine agonists for the different Swedish counties in 2001 varied between 1.52 and 2.44 and 0.13 and 0.74 DDD/1000 inhabitants and day, respectively. There was no correlation, whether positive or negative, between the sales of dopamine agonists, levodopa and COMT inhibitors or between the sales and the densities of neurologists. CONCLUSION: The consumption of levodopa in Sweden continues to increase in spite of a dramatic increase in the utilisation of dopamine agonists and the introduction of COMT-inhibitors.

Catechol O-Methyltransferase Inhibitors↗
PubMed2006

Warriors versus worriers: the role of COMT gene variants.

Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.

Adult↗
PubMed2005

Molecular genetics support Gray's personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system.

The present study provides the first direct molecular genetics support for Gray's Reinforcement Sensitivity Theory (RST), which is one of the most influential biologically oriented personality theories. It was investigated whether the DRD2 TaqIA and the COMT polymorphisms were related to the dimensions of Gray's personality theory, as measured by the Carver and White BIS/BAS scales. In a sample of 295 healthy subjects results revealed significant DRD2xCOMT interactions (i.e. epistasis) for the total BAS scale (related to positive emotionality) and for the subscales Drive (D) and Fun Seeking (FS). High BAS scores were observed if the catabolic enzyme activity and the D2 receptor density as indicated by the two polymorphisms were in disequilibrium, i.e. in the presence of the Val-/A1- (low enzyme activity/high receptor density) or the Val+/A1+ (high enzyme activity/low receptor density) alleles. In a random subsample (n=48), it could be demonstrated that those allele combinations of COMT and DRD2 associated with high BAS scores also had significantly lower prolactin levels under resting conditions, indicating high dopamine activity, compared to those allele combinations with low BAS scores. Furthermore, two-way interactions of DRD2 TaqIAxsmoking status and of the Met allele of COMTxsmoking status on FS and Metxgender on BIS could be shown.

Adult↗
PubMed2005

Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype.

Using multimodal neuroimaging in humans, we demonstrate specific interactions between prefrontal activity and midbrain dopaminergic synthesis. A common V(108/158)M substitution in the gene for catecholamine-O-methyltransferase (COMT), an important enzyme regulating prefrontal dopamine turnover, predicted reduced dopamine synthesis in midbrain and qualitatively affected the interaction with prefrontal cortex. These data implicate a dopaminergic tuning mechanism in prefrontal cortex and suggest a systems-level mechanism for cognitive and neuropsychiatric associations with COMT.

Adult↗
PubMed2003

Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone.

Risperidone is a widely used atypical antipsychotic with certain advantages over typical antipsychotics. Although variations in the efficacy of treatment with risperidone have been observed, no specific predictable marker has been identified as of yet. In all, 73 Japanese patients with schizophrenia were given risperidone for 8 weeks, and clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Six candidate polymorphisms (HTR2A -1438G>A, 102T>C, H452Y; DRD2 -141delC, Taq I A; COMT V158M) were genotyped. The diplotype configuration for each individual was estimated by the maximum-likelihood method. Multiple linear regressions were used to analyze the effects of these haplotypes/genotype and other prognostic factors on PANSS scale performance. After adjustment for the effects of patient-related variables, HTR2A diplotype and COMT genotype, as well as other potential prognostic factors, did not significantly influence the clinical performance. A DRD2 haplotype tended to correlate with better clinical performance. Compared with patients who had Ins-A2/Ins-A2 diplotype (n=25), PANSS total scores of patients with Ins-A2/Del-A1 diplotype (n=10) showed 40% greater improvement (P=0.03). The PANSS total scores of patients with HTR2A A-T/A-T diplotype (n=22) tended to show 15% worse improvement compared with A-T/G-C diplotype (n=33) (P=0.06). These results should be treated with caution because of limitations due to small sample size, heterogeneity of patients with respect to past antipsychotic use history, and no correction for multiple corrections. However, the present findings generate important hypotheses in a sample of Japanese schizophrenia patients that may lay the foundation for future pharmacogenomics investigations in other populations.

Adult↗
PubMed2004

Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder.

Family and twin studies have supported a strong genetic factor in the etiology of obsessive-compulsive disorder (OCD), although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. In this cross-sectional study, we have examined the allelic and genotypic frequencies of a Val-158-Met substitution in the COMT gene, a 44-base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5-HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects. There were no observed differences in the frequencies of allele and genotype between patients and control groups for the COMT, the 5HTTLPR and the T102C 5HT2A gene polymorphisms. In contrast, a statistically significant difference between OCD patients and controls was observed on the genotypic distribution (chi(2) = 16.7, 2df, P = 0.0002) and on the allelic frequencies (chi(2) = 15.8, 1df, P = 0.00007) for the C516T 5HT2A gene polymorphism. The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in our sample. However, further studies using larger samples and family based methods are recommended to confirm these findings.

Adult↗
PubMed2004

Hypnotic susceptibility: multidimensional relationships with Cloninger's Tridimensional Personality Questionnaire, COMT polymorphisms, absorption, and attentional characteristics.

One hundred and seven healthy volunteers were administered Cloninger's Tridimensional Personality Questionnaire (TPQ), the Differential Attentional Processes Inventory (DAPI), the Tellegen Absorption Scale (TAS), and the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C). Polymorphisms of catechol O-methyltransferase (COMT), an enzyme involved in dopamine metabolism, were assessed. Highly hypnotizable subjects self-reported greater TPQ persistence, absorption, and focused attentional abilities. Hierarchical multiple regression analyses found that TPQ persistence, COMT, TAS, and the DAPI attentional scales explained 43.8% of the variance in women and 29% in men. Membership was correctly discriminated for the more extreme low (62.1%) and highly (81.5%) hypnotizable groups. These results suggest that highly hypnotizable persons have a more effective frontolimbic attentional system and further suggest the involvement of dopaminergic systems in hypnotizability.

Adolescent↗
PubMed2004

Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk.

Tobacco smoking and occupational exposure are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines, which lead to oxidative stress and DNA damage. Several enzymes, which play key roles in oxidative stress are polymorphic in humans. Myeloperoxidase (MPO) produces a strong oxidant for microbicidal activity, and activates carcinogens in tobacco smoke. Catechol-O-methyltransferase (COMT) catalyzes the methylation of endo- and xenobiotics and prevents redox cycling. NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two-electron reduction of quinoid compounds, which also protects cells from redox cycling. Manganese superoxide dismutase (MnSOD) protects cells from free radical injury. To test the hypothesis that the risk of bladder cancer can be influenced by polymorphisms in the genes that modulate oxidative stress, in particular by interacting with environmental carcinogens, we conducted a hospital-based case-control study among men in Brescia, Northern Italy. We recruited and interviewed 201 incident cases and 214 controls from 1997 to 2000. Occupational exposures to PAHs and aromatic amines were coded blindly by occupational physicians. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk and the effect of modifications of smoking and occupational exposures were evaluated. MPO G-463A homozygous variant was associated with a reduced risk of bladder cancer with an OR of 0.31 (95% CI = 0.12-0.80). MnSOD Val/Val genotype increased the risk of bladder cancer with OR of 1.91 (95% CI = 1.20-3.04), and there was a combined effect with smoking (OR = 7.20, 95% CI = 3.23-16.1) and PAH (OR = 3.02, 95% CI = 1.35-6.74). We did not observe an effect of COMT Val108Met polymorphism. These findings suggest that individual susceptibility of bladder cancer may be modulated by MPO and MnSOD polymorphisms, and that the combination of genetic factors involved in oxidative stress response with environmental carcinogens may play an important role in bladder carcinogenesis.

Adult↗
PubMed2006

Bipolar 1 disorder is not associated with the RGS4, PRODH, COMT and GRK3 genes.

Although current psychiatric nosology separates bipolar disorder and schizophrenia into non-overlapping categories, there is growing evidence of a partial aetiological overlap between them from linkage, genetic epidemiology and molecular genetics studies. Thus, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. In this study we investigated a total of 15 single nucleotide polymorphisms (SNPs), and all possible haplotypes, of genes that have been previously implicated in schizophrenia or bipolar disorder - RGS4, PRODH, COMT and GRK3 - in a sample of 213 cases with bipolar affective disorder type 1 and 197 controls from Scotland. We analysed the polymorphisms allele-wise, genotype-wise and, for each gene, haplotype-wise but obtained no result that reached nominal significance (p<0.05) for an association with the disease status. In conclusion, we could not find evidence of association between RGS4, PRODH, COMT and GRK3 genes and bipolar affective disorder 1 in the Scottish population.

Bipolar Disorder↗
PubMed1991

COMT inhibition with nitecapone does not affect the tyramine pressor response.

Nitecapone (OR-462) is a new selective COMT inhibitor with gastroprotective properties. The aim of the present study was to determine whether nitecapone potentiates the haemodynamic effects of a tyramine-induced increase in catecholamine release. The systolic blood pressure response to tyramine was studied in 11 healthy male volunteers (age 20-32 years). Tyramine was given i.v. as rapid bolus injections in increasing doses without drug intake and after oral intake of single doses of 25 mg and 100 mg of nitecapone. The tyramine dose required to increase systolic blood pressure by 30 mm Hg ('pressor dose') was 4.98 mg, 5.04 mg and 4.88 mg after no medication, and with 25 mg and 100 mg of nitecapone, respectively. There were also no differences in the systolic blood pressure response vs time curves between the three regimens. COMT inhibition with nitecapone did not potentiate the haemodynamic responses to tyramine-induced catecholamine release.

Adult↗
PubMed1983

MAO COMT, and GABA-T activities in primary astroglial cultures.

Cultures from cerebral hemispheres of newborn rats contain the enzymes monoamine oxidase (MAO), catechol-O-methyltransferase (COMT), and gamma-aminobutyric acid alpha-ketoglutarate transaminase (GABA-T). The COMT activity was higher in the cultures than in adult rat cerebral hemispheres. The MAO activity was comparable in the cultures and in the rat cerebral hemispheres. The activities of both these enzymes increased with age in the cultures and in the rat brain hemispheres. In the culture the activities were further potentiated by removal of fetal calf serum and addition of 0.1 mM dibutyryl-cyclic AMP (dB-cAMP). GABA-T activity was, however, lower in the cultures than in the adult rat brain hemispheres. The activity increased in brain during postnatal maturation. No changes in the enzyme activity were observed in the cultures, either during growth or after removal of fetal calf serum and addition of dB-cAMP.

4-Aminobutyrate Transaminase↗
PubMed1981

Comparison of MAO, D beta H, and COMT activities in chronic schizophrenics selected on the basis of nailfold capillary pattern.

A group of 17 white male chronic schizophrenic subjects were divided on the basis of plexus visualization score (PVS). High and low PVS subjects were compared to each other and to low PVS controls on measures of platelet monamine oxidase (MAO), rbc catechol-o-methyl transferase (COMT), and plasma dopamine-beta-hydroxylase (D beta H). There were no differences between high and low PVS subjects on any biochemical variable. Schizophrenic subjects had lower platelet MAO activity than controls. Platelet MAO and rbc COMT were significantly correlated in schizophrenic subjects.

Adult↗
PubMed2006

The molecular genetics of cognition: dopamine, COMT and BDNF.

The important contribution of genetic factors to the development of cognition and intelligence is widely acknowledged, but identification of these genes has proven to be difficult. Given a variety of evidence implicating the prefrontal cortex and its dopaminergic circuits in cognition, most of the research conducted to date has focused on genes regulating dopaminergic function. Here we review the genetic association studies carried out on catechol-O-methyltransferase (COMT) and the dopamine receptor genes, D1, D2 and D4. In addition, the evidence implicating another promising candidate gene, brain-derived neurotrophic factor (BDNF) in neuropsychological function, is assessed. Both the COMT val158met polymorphism and the BDNF val66met variant appear to influence cognitive function, but the specific neurocognitive processes involved continue to be a matter of debate. Part of the difficulty is distinguishing between false positives, pleiotropy and the influence of a general intelligence factor, g. Also at issue is the complexity of the relevant neuromolecular pathways, which make the inference of simple causal relationships difficult. The implications of molecular genetic cognitive research for psychiatry are discussed in light of these data.

Animals↗