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A variety of evidence suggests that, among humans, the individual tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or Now bias, varies with frontal dopamine (DA) levels. As cyclic elevations in estradiol (E+) modulate other frontal DA-dependent behaviors, we tested ovarian cycle effects on Now bias, and whether any such effects are E+ mediated. To do so, we quantified Now/Later choice behavior in naturally cycling adult females (n = 87; ages 18-40 years) during both the menstrual phase (MP; cycle day 1-2; low E+), and the follicular phase (FP; cycle day 11-12; high E+). Now bias decreased an average of 3.6% from MP to FP (p = 0.006). Measures of salivary E+ levels at each visit were available in a subsample of participants (n = 34). Participants with a verified E+ rise from MP to FP showed significantly greater decreases in Now bias at mid-cycle (n = 23) than those without a rise (n = 11; p = 0.03); Now bias decreased an average of 10.2% in the E+ rise group but increased an average of 7.9% in the no E+ rise group. The change in Now bias from MP to FP inversely correlated with the change in E+ (ρ = -0.39; p = 0.023), an effect driven by individuals with putatively lower frontal DA based on genotype at the Val(158)Met polymorphism in the COMT gene. This is the first demonstration that intertemporal choice varies across the ovarian cycle, with Now bias declining at mid-cycle, when fertility peaks. Moreover, our data suggest that the interacting effects of estradiol and frontal DA mediate this cycle effect on decision making.
BACKGROUND - The catechol-O-methyltransferase (COMT) enzyme has been widely studied due to its multiple roles in neurological functioning, estrogen biology, and methylation metabolic pathways. Numerous studies have investigated variation in the large COMT gene, with the majority focusing on single nucleotide polymorphisms (SNPs). This body of work has linked COMT genetic variation with a vast array of conditions, including several neurobehavioral disorders, pain sensitivity, and multiple human cancers. Based on COMT's numerous biological roles and recent studies suggesting that methylation of the COMT gene impacts COMT gene expression, we comprehensively interrogated methylation in over 200 CpG dinucleotide sequences spanning the length of the COMT gene.
METHODS - Using saliva-derived DNA from a non-clinical sample of human subjects, we tested for associations between COMT CpG methylation and factors reported to interact with COMT genetic effects, including demographic factors and alcohol use. Finally, we tested associations between COMT CpG methylation state and COMT gene expression in breast cancer cell lines. We interrogated >200 CpGs in 13 amplicons spanning the 5' UTR to the last exon of the CpG dinucleotide-rich COMT gene in n = 48 subjects, n = 11 cell lines and 1 endogenous 18S rRNA control.
RESULTS - With the exception of the CpG island in the 5'UTR and 1st exon, all other CpG islands were strongly methylated with typical dynamic ranges between 50-90%. In the saliva samples, methylation of multiple COMT loci was associated with socioeconomic status or ethnicity. We found associations between methylation at numerous loci and genotype at the functional Val158Met SNP (rs4680), and most of the correlations between methylation and demographic and alcohol use factors were Val158Met allele-specific. Methylation at several of these loci also associated with COMT gene expression in breast cancer cell lines.
CONCLUSIONS - We report the first comprehensive interrogation of COMT methylation. We corroborate previous findings of variation in COMT methylation with gene expression and the Val158Met genotype, and also report novel associations with socioeconomic status (SES) and ethnicity at several methylated loci. These results point to novel mechanisms for COMT regulation, which may have broad therapeutic implications.
There has been recent controversy regarding predictors of cisplatin-induced ototoxicity in children, as highlighted in a previous issue of this journal. We have reviewed the two articles that purport to show an association between TPMT and COMT variants and ototoxicity, as well as the related patent applications dating back to 2006. We summarize statistical issues not fully addressed by the authors that appear to have confounded the results of their studies.
We have recently demonstrated that intrarenal dopamine plays an important role in preventing the development of systemic hypertension. Similarly, renal cytochrome P-450 (CYP)-epoxygenase-derived arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs), also are antihypertensive through inhibiting sodium reabsorption and vasodilation. The potential interaction between renal dopamine and epoxygenase systems was investigated. Catechol-O-methyl-transferase (COMT)(-/-) mice with increased intrarenal dopamine levels and proximal tubule deletion of aromatic amino acid decarboxylase (ptAADC(-/-)) mice with renal dopamine deficiency were treated with a low-salt diet or high-salt diet for 2 wk. Wild-type or Cyp2c44(-/-) mice were treated with gludopa, which selectively increased renal dopamine levels. In low salt-treated mice, urinary EET levels were related to renal dopamine levels, being highest in COMT(-/-) mice and lowest in ptAADC(-/-) mice. In high salt-treated mice, total EET and individual EET levels in both the kidney and urine were also highest in COMT(-/-) mice and lowest in ptAADC(-/-) mice. Selective increases in renal dopamine in response to gludopa administration led to marked increases in both total and all individual EET levels in the kidney without any changes in blood levels. qRT-PCR and immunoblotting indicated that gludopa increased renal Cyp2c44 mRNA and protein levels. Gludopa induced marked increases in urine volume and urinary sodium excretion in wild-type mice. In contrast, gludopa did not induce significant increases in urine volume or urinary sodium excretion in Cyp2c44(-/-) mice. These studies demonstrate that renal EET levels are maintained by intrarenal dopamine, and Cyp2c44-derived EETs play an important role in intrarenal dopamine-induced natriuresis and diuresis.
Frontal-dependent task performance is typically modulated by dopamine (DA) according to an inverted-U pattern, whereby intermediate levels of DA signaling optimizes performance. Numerous studies implicate trait differences in DA signaling based on differences in the catechol-O-methyltransferase (COMT) gene in executive function task performance. However, little work has investigated genetic variations in DA signaling downstream from COMT. One candidate is the DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the D1-type DA receptor, the dominant DA receptor in the frontal cortex. Using an n-back task, we used signal detection theory to measure performance in a healthy adult population (n = 97) genotyped for single nucleotide polymorphisms in the COMT (rs4680) and DARPP-32 (rs907094) genes. Correct target detection (hits) and false alarms were used to calculate d' measures for each working memory load (0-, 2-, and 3-back). At the highest load (3-back) only, we observed a significant COMT × DARPP-32 interaction, such that the DARPP-32 T/T genotype enhanced target detection in COMT(ValVal) individuals, but impaired target detection in COMT(Met) carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMT(ValVal)) but impairs target detection in those with putatively higher frontal DA levels (COMT(Met) carriers). Moreover, these data support an inverted-U model with intermediate levels of DA signaling optimizing performance on tasks requiring maintenance of mental representations in working memory.
The kidney has a local intrarenal dopaminergic system, and in the kidney, dopamine modulates renal hemodynamics, inhibits salt and fluid reabsorption, antagonizes the renin-angiotensin system, and inhibits oxidative stress. The current study examined the effects of alterations in the intrarenal dopaminergic system on kidney structure and function in models of type 1 diabetes. We studied catechol-O-methyl-transferase (COMT)(-/-) mice, which have increased renal dopamine production due to decreased dopamine metabolism, and renal transplantation was used to determine whether the effects seen with COMT deficiency were kidney-specific. To determine the effects of selective inhibition of intrarenal dopamine production, we used mice with proximal tubule deletion of aromatic amino acid decarboxylase (ptAADC(-/-)). Compared with wild-type diabetic mice, COMT(-/-) mice had decreased hyperfiltration, decreased macula densa cyclooxygenase-2 expression, decreased albuminuria, decreased glomerulopathy, and inhibition of expression of markers of inflammation, oxidative stress, and fibrosis. These differences were also seen in diabetic mice with a transplanted kidney from COMT(-/-) mice. In contrast, diabetic ptAADC(-/-) mice had increased nephropathy. Our study demonstrates an important role of the intrarenal dopaminergic system to modulate the development and progression of diabetic kidney injury and indicate that the decreased renal dopamine production may have important consequences in the underlying pathogenesis of diabetic nephropathy.
RATIONALE AND OBJECTIVE - A form of impulsivity, the tendency to choose immediate over delayed rewards (delay-discounting) has been associated with a single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene (COMTval¹⁵⁸met; rs4680). However, the existing data regarding the nature of this association are in conflict. We have previously reported that adults homozygous for valine (val) at the COMTval¹⁵⁸met SNP demonstrate greater delay-discounting than do methionine (met) allele carriers (Boettiger et al., J Neurosci 27:14383-14391, 2007). In contrast, a recent study of adolescent males found that those with the met/met genotype demonstrate greater delay-discounting than do val-allele carriers (Paloyelis et al., Neuropsychopharmacology 35:2414-2426, 2010). Based on reported age-related changes in frontal dopamine function and COMT expression, we hypothesized that the association of COMT genotype with delay-discounting behavior is modulated by age from late adolescence to young adulthood.
METHODS - To test this hypothesis, we genotyped late adolescents (18-21 years; n = 72) and adults (22-40 years; n = 70) for the COMTval¹⁵⁸met polymorphism, measured their delay-discounting behavior, and tested for an interaction between age group and COMT genotype.
RESULTS - This cross-sectional study found that age modulates COMTval¹⁵⁸met genotype effects on delay-discounting behavior. Among met-carriers, delay-discounting was negatively correlated with age from late adolescence to adulthood, while among val/val individuals delay-discounting was positively correlated with age across this range.
CONCLUSIONS - These results confirm our previous finding of enhanced delay-discounting among val/val adults relative to met-allele carriers, and help reconcile existing literature. We propose a single U-shaped model of the relationship between frontal DA levels and impulsive choice that accounts for both adolescent and adult data.
It is well-recognized that excessive angiotensin II (ANG II) can mediate progressive renal injury. Previous studies by us and others have indicated that dopamine may modulate actions of ANG II in the kidney. The current studies investigated whether altering intrarenal dopamine levels affected ANG II-mediated renal fibrosis. We utilized a model of increased intrarenal dopamine, catechol-O-methyl-transferase knockout (COMT KO) mice, which have increased kidney dopamine levels due to deletion of a major intrarenal dopamine-metabolizing enzyme. In wild-type mice, chronic ANG II infusion increased renal expression of both of the major dopamine-metabolizing enzymes, COMT and monoamine oxidase. After 8 wk of ANG II infusion, there were no significant differences in blood pressure between wild-type and COMT KO mice. Compared with wild-type, COMT KO mice had decreased albuminuria and tubulointerstitial injury. In response to ANG II infusion, there was decreased expression of both glomerular and tubulointerstitial injury markers (fibronectin, connective tissue growth factor, fibroblast-specific protein-1, collagen I, podocyte vascular endothelial growth factor) in COMT KO mice. We recently reported that ANG II-mediated tubulointerstitial fibrosis is mediated by src-dependent epidermal growth factor receptor (EGFR) activation. In aromatic l-amino acid decarboxylase knockout (AADC KO) mice, a model of intrarenal dopamine deficiency due to selective proximal tubule AADC deletion, which inhibits intrarenal dopamine synthesis, ANG II infusion further increased expression of p-src and pTyr845-EGFR. In contrast, their expression was markedly attenuated in COMT KO mice. These results demonstrate a role for intrarenal dopamine to buffer the detrimental effects of ANG II upon the kidney.
Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale≤6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.