Catechol-O-Methyltransferase Activity in Individuals with Substance Use Disorders: A Case Control Study

Background Impulsivity and substance use disorders (SUD) can be related to the same environmental factors. In this study, we intended to evaluate the dopaminergic function in imprisoned SUD offenders through the determination of s-COMT activity. Methods The study included 46 male individuals from a Portuguese penal institution. The participants were assessed through a battery of standardised instruments: Psychopathy Checklist-Revised (PCL-R), Barratt Impulsivity Scale Version 11 (BIS-11), and the European version of the Addiction Severity Index (EuropASI). s-COMT erythrocyte activity was evaluated. Results Overall, 73.9% (n=34) of the individuals had Antisocial Personality Disorder (ASPD) and 58.7% (n=27) presented SUDs. We evidenced, for the first time, that, in SUD individuals, s-COMT activity is correlated with the severity of drug dependence (EuropASI) (p<0.05), and with BIS-11 factors self-control (p<0.0001) and non-planning (p=0.002). Conclusions This study opens new perspectives regarding the pharmacological intervention on drug dependence through the interference on dopamine pathways.

The Associations between COMT and MAO-B Genetic Variants with Negative Symptoms in Patients with Schizophrenia

Negative symptoms of schizophrenia, including anhedonia, represent a heavy burden on patients and their relatives. These symptoms are associated with cortical hypodopamynergia and impaired striatal dopamine release in response to reward stimuli. Catechol-O-methyltransferase (COMT) and monoamine oxidase type B (MAO-B) degrade dopamine and affect its neurotransmission. The study determined the association between COMT rs4680 and rs4818, MAO-B rs1799836 and rs6651806 polymorphisms, the severity of negative symptoms, and physical and social anhedonia in schizophrenia. Sex-dependent associations were detected in a research sample of 302 patients with schizophrenia. In female patients with schizophrenia, the presence of the G allele or GG genotype of COMT rs4680 and rs4818, as well as GG haplotype rs4818-rs4680, which were all related to higher COMT activity, was associated with an increase in several dimensions of negative symptoms and anhedonia. In male patients with schizophrenia, carriers of the MAO-B rs1799836 A allele, presumably associated with higher MAO-B activity, had a higher severity of alogia, while carriers of the A allele of the MAO-B rs6651806 had a higher severity of negative symptoms. These findings suggest that higher dopamine degradation, associated with COMT and MAO-B genetic variants, is associated with a sex-specific increase in the severity of negative symptoms in schizophrenia patients.

Dietary Magnesium Insufficiency Induces Salt-Sensitive Hypertension in Mice Associated With Reduced Kidney Catechol-O-Methyl Transferase Activity

COMT (Catechol-O-methyl transferase), an enzyme that metabolizes catechol, requires magnesium (Mg2+) to maintain its activity. Low COMT activity causes insufficient 2-methoxyestradiol (2-ME), a biologically active metabolite from hydroxyestradiol, which leads to hypertensive disorders, including preeclampsia. Hypoestrogenism increases the risk of salt-sensitive hypertension (SSH). SSH and preeclampsia are risk factors for each other; however, the molecular mechanism of this interaction is unclear. We focused on the interactive effect of Mg2+insufficiency and genetic COMT deficiency on SSH using 2 strains of mice with genetically distinct COMT activity. In male mice, BL6 (C57BL/6J), a high-activity COMT strain, displayed unaltered blood pressure regardless of the Mg2+and salt levels in food; DBA (DBA/2J), a low-activity COMT strain, developed SSH under low Mg2+and high-salt conditions. COMT inhibition in C57BL/6J strain also induced SSH. Treatment with 2-ME ameliorated SSH in both models. The ATR1 (angiotensin II type 1 receptor)–STE20-SPAK (serine-proline alanine-rich kinase)–NCC (sodium chloride cotransporter) axis, molecules associated with sodium reabsorption in distal convoluted tubules, was activated in mice that developed SSH. In female DBA mice, ovariectomized mice displayed SSH under low Mg2+associated with activation of ATR1-SPAK-NCC axis; 2-ME inhibited all, whereas the blood pressure of sham mice was unaltered regardless of any intervention. Our findings revealed that Mg2+insufficiency exaggerated the low COMT activity and induced SSH via the ATR1-SPAK-NCC axis due to 2-ME insufficiency, suggesting a new pathophysiological role that links COMT/2-ME deficiency with hypertensive syndrome.

Evaluation of Phenotypic and Genotypic Variations of Drug Metabolising Enzymes and Transporters in Chronic Pain Patients Facing Adverse Drug Reactions or Non-Response to Analgesics: A Retrospective Study

This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients.

S176. A PRELIMINARY INVESTIGATION OF COMT GENE INVOLVEMENT IN COGNITIVE FLEXIBILITY AND ATTENTION IN SCHIZOPHRENIA SPECTRUM DISORDERS

Background Schizophrenia spectrum disorders (SSD) are often characterised by a plateau or decline in cognitive abilities early in the prodrome. The cause of developmental alteration remains unknown, and investigation of genetic involvement in cognitive function in these disorders may assist the understanding of the underlying neurobiological mechanisms involved. Variation at two single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) gene have previously shown an influence on COMT protein levels and cognition; rs4680 and rs4818. Here we investigate the influence of the nonsynonymous “Val/Met” SNP rs4680 and a second functional SNP, rs4818, on tasks of cognitive flexibility and attention. Methods The sample comprised 48 healthy controls (HC; age = 31.95 ± 12.80; 25 males, 23 females), and 43 with a diagnosis of SSD (age = 41.64 ± 10.36; 26 males, 17 females). Measures of cognitive flexibility and attention included the Wisconsin Card Sorting Test (WCST), Continuous Performance Test-Identical Pairs version (CPT-IP), Trail Making Test (TMT), and the D-KEFS Colour Word Interference Test (CWIT). Due to small cohort sizes, in our preliminary analyses we chose to compare people who should be most severely affected because of inheriting COMT haplotypes associated with poor cognitive functioning (GG rs4818 / GG rs4680: G-G haplotype) to those with haplotypes associated with better cognitive functioning (CC rs4818 / AA rs4680: C-A haplotype). Multivariate analysis of variance factors included COMT haplotype, diagnosis (HC and SSD), and gender, with Bonferroni correction for multiple comparisons; age was included as a covariate. Analyses were also conducted based on a non-functional SNP of the COMT gene; rs165599, as a negative control. Results SSD exhibited reduced cognitive performance compared to HC; F(4, 75) = 8.810, p &lt; .001. Investigation of C-A haplotype revealed an interaction with diagnosis on cognitive performance; F(8, 154) = 2.075, p = .041; SSD had reduced performance compared to HC for the WCST, CPT-IP, and TMT in C-A haplotypes (all p &lt; .05). COMT haplotype also interacted with gender on cognitive performance (C-A haplotype; F(8, 154) = 2.315, p = .023, G-G haplotype; F(8, 154) = 2.706, p = .008). Males who were C-A non-carriers and /or G-G haplotype (high COMT activity groups) performed better on CPT-IP (both p &lt; .05) and worse on CWIT (both p &lt; .05) compared to females. Control SNP rs165599 revealed no main effects or significant interactions (all p &gt; .05). Discussion The role of the COMT gene in the cognitive abilities of SSD remains contentious as gene expression does not differ from a healthy population. This preliminary analysis revealed an interaction between diagnosis and COMT haplotype, however, this only reached statistical significance for the C-A haplotype, where SSD with C-A haplotype and C-A non-carriers had reduced performance compared to HC on most tasks except TMT. The different effects found across the tasks, which probed various elements of cognitive flexibility and attention, supports a nuanced role of COMT in cognitive function. Further, high COMT activity was beneficial for males on CPT-IP but not CWIT compared to females. Gender interaction remains a significant consideration in studies of the COMT gene, likely involving the catechol-estrogens which are substrates of COMT. As expected there was no significant results with control SNP rs165599, indicating that findings were due to the influence of SNPs rs4680 and rs4818 on COMT activity.