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PubMed2001

BIA 3-202, a novel catechol-O-methyltransferase inhibitor, enhances the availability of L-DOPA to the brain and reduces its O-methylation.

1-[3,4-Dihydroxy-5-nitrophenyl]-2-phenyl-ethanone (BIA 3-202) is a new long-acting catechol-O-methyltransferase (COMT) inhibitor with limited access to the brain. The present study evaluated the interference of BIA 3-202 upon levels of L-3,4-dihydroxyphenylalanine (L-DOPA) and metabolites in plasma (3-O-methyl-L-DOPA) and brain [3-O-methyl-L-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] in rats orally treated with L-DOPA (20 mg/kg) plus benserazide (30 mg/kg). At different time points (1, 3 and 6 h) after the administration of BIA 3-202 (0, 3, 10 and 30 mg/kg) or L-DOPA plus benserazide, rats were sacrificed and the right striatum was quickly dissected out and stored for the assay of L-DOPA, 3-O-methyl-L-DOPA, dopamine and amine metabolites. Levels of L-DOPA, 3-O-methyl-L-DOPA, dopamine, DOPAC and HVA in the striatum in L-DOPA plus benserazide-treated rats were higher than in vehicle-treated rats. However, this increase in striatal L-DOPA, dopamine, DOPAC and HVA was, in a dose- and time-dependent manner, even higher (P<0.05) in rats given BIA 3-202 (3, 10 and 30 mg/kg). This effect was accompanied by a marked decrease in 3-O-methyl-L-DOPA levels in the striatum of L-DOPA plus benserazide-treated rats. Increases in levels of L-DOPA and decreases in 3-O-methyl-L-DOPA levels in plasma also accompanied the administration of BIA 3-202. BIA 3-202 did not significantly affect levels of DOPAC and HVA in the striatum in vehicle-treated rats. It is concluded that administration of BIA 3-202 enhances the availability of L-DOPA to the brain by reducing its O-methylation in the periphery, which may prove beneficial in parkinsonian patients treated with L-DOPA plus an aromatic amino acid decarboxylase inhibitor.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

4-Hydroxycatecholestrogen metabolism responses to exercise and training: possible implications for menstrual cycle irregularities and breast cancer.

OBJECTIVE: To investigate the behavior of C4-substituted estrogens, the so-called catecholestrogens, in response to acute exercise and training. The 4-hydroxyestrogens are known to have both a strong estrogenic potency and affinity for catechol-O-methyltransferase (COMT), the enzyme that deactivates catecholamines. DESIGN: A prospective trial covering three menstrual cycles: a control cycle, a moderate training cycle, and a heavy training cycle. PARTICIPANT(S): Six untrained, healthy, eumenorrheic women (mean pretraining maximum oxygen uptake: 40.9 +/- 4.9 mL/kg per minute, body fat: 27.9% +/- 3.6%) volunteered for this study. INTERVENTION(S): An incremental exercise test to exhaustion on a cycle ergometer, in the follicular and luteal phases, before and after a brief but exhaustive training program. MAIN OUTCOME MEASURE(S): Hormone measurements included follicular and luteal phase plasma E2, LH, catecholamines, PRL, total unconjugated and conjugated estrogens, total 4-hydroxyestrogens (4-OHE), and 4-hydroxyestrogen-monomethylethers (4-MeOE). RESULT(S): Pretraining baseline 4-OHE levels were significantly higher in the luteal phase (66 +/- 9 pg/mL; mean +/- SEM) than in the follicular phase (51 +/- 7 pg/mL). Pretraining and post-training baseline 4-MeOE values were below minimal detection limits (< 35 pg/mL). During incremental exercise, catecholamines, PRL, E2, unconjugated and conjugated estrogens, 4-OHE, and 4-MeOE always increased (the increases in 4-OHE during exercise were more pronounced before training, contrary to the 4-MeOE being most increased after training). The baseline 4-MeOE:4-OHE ratio (a measure of catecholestrogen activity) significantly increased with progressive training. CONCLUSION(S): Because 4-OHE have been shown to be able to control the hypothalamic gonadotropin oscillator and to stimulate the luteolytic prostaglandin PGF2 alpha, the acute exercise-induced increases of 4-OHE and their positive correlation with lactate levels may indicate a key process in the pathogenesis of exercise-associated menstrual irregularities. In addition, 4-OHE, when insufficiently O-methylated, are known to be capable of raising mutagenic superoxide free radicals and causing DNA damage that may lead to breast cancer. The results of the present study also may be of significance for the apparent protective effects of sports participation against cancer of the breast.

Adult↗
PubMed2002

Rats fed a high sucrose diet have altered heart antioxidant enzyme activity and gene expression.

Several studies in human and animal models have shown that consumption of fructose facilitates oxidative damage but the mechanisms involved are unclear. In this study, the effects of two weeks of high sucrose on both oxidative stress parameters and stress-related gene expression, using a cDNA array, were investigated in rat heart. Both increased TBARS and lower Cu-Zn-SOD activity were found in heart from high sucrose fed rats compared to rats on a starch diet. Higher plasma NO level was also found in the high sucrose group, corroborating the pro-oxidant effect of fructose. The Cu-Zn-SOD mRNA level was also greater in the high sucrose group; the Mn-SOD, GPX and catalase were not different between the two groups. Increased HSP70 and decreased COMT genes expression were observed, underlying the hypertensive effect of dietary fructose. These findings confirm the pro-oxidant effect of high sucrose feeding to rats and highlight the NO/O(2)(*-) balance importance in oxidative homeostasis.

Animals↗
PubMed1999

Monoamine oxidase and catechol-O-methyltransferase inhibitors.

Despite advances in the treatment of PD, there remain significant unmet therapeutic needs. This is particularly true at the later stages of the disease when dopaminergic therapy is complicated by motor fluctuations and dyskinesias. Inhibition of dopamine metabolism is a valuable adjunct to exogenous dopaminergic replacement. Inhibitors of MAO-B have been used to treat early and advanced PD for a number of years. Although controversy remains, existing evidence still raises the possibility that MAO-B inhibition may confer a protective effect in PD, delaying the progression of the underlying pathology. More recently, clinically useful inhibitors of COMT have become available. These medications largely act peripherally to increase the pool of available dopamine precursor and prolong the duration of effect of L-dopa. They are indicated primarily for control of motor fluctuations.

Benzophenones↗
PubMed2001

Genetic susceptibility and environmental estrogen-like compounds.

Environmental chemicals with estrogenic activities have been suggested to be able to interact with the endocrine system. Endogenous estrogen is synthesized in the ovarian theca cells of premenopausal women or in the stromal adipose cells of the breast of postmenopausal women and minor quantities in peripheral tissue. These cells, as well as breast tissue, express all the necessary enzymes for this synthesis, CYP17, CYP11a, CYP19, 17-beta-hydroxysteroid hydrogenase, steroid sulfatase as well as enzymes further hydroxylating estradiol, such as CYP1A1, CYP3A4, CYP1B1, catechol-o-methyltransferase (COMT). Polymorphisms in these enzymes may have a possible role in the link between environmental estrogens and hormone-like substances and the interindividual risk of breast cancer.

Aromatase↗
PubMed1999

Interaction between L-DOPA and 3-O-methyl-L-DOPA for transport in immortalised rat capillary cerebral endothelial cells.

The present study aimed to determine the kinetics of L-3,4-dihydroxyphenylalanine (L-DOPA) uptake in an immortalised cell line of rat capillary cerebral endothelial cells (clones RBE 4 and RBE 4B), to define the type of interaction with 3-O-methyl-L-DOPA (3-OM-L-DOPA), sensitivity to 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BHC), N-(methylamino)-isobutyric acid (MeAIB) and sodium. Non-linear analysis of the saturation curves for L-DOPA and 3-OM-L-DOPA revealed in RBE 4 cells Km values (in microM) of 72 (53, 91) and 40 (25, 57) and in RBE 4B cells Km values (in microM) of 60 (46, 74) and 44 (13, 75), respectively. IC50 values for 3-OM-L-DOPA (RBE 4, 642 [542, 759] microM; RBE 4B, 482 [475, 489] microM) obtained in the presence of a nearly saturating (250 microM) concentration of L-DOPA were greater than the corresponding Ki values (RBE 4, 143 [121, 170] microM; RBE 4B, 93 [92, 95] microM) obtained in the presence of a nearly saturating (250 microM) concentration of 3-OM-L-DOPA; this is compatible with a competitive type of interaction between L-DOPA and 3-OM-L-DOPA. Uptake of both L-DOPA and 3-OM-L-DOPA in RBE 4 and RBE 4B cells was sensitive to BHC with similar IC50 values. MeAIB (up to 2.5 mM) was found not to interfere with the uptake of both L-DOPA and 3-OM-L-DOPA. Uptake of (250 microM) L-DOPA and 3-OM-L-DOPA in the absence of sodium in the incubation medium was similar to that observed in the presence of increasing concentrations of sodium (20-140 mM). Homogenates of both cell lines were endowed with considerable COMT activity. Incubation of RBE 4 and RBE 4B cells with L-DOPA (25 microM) in the presence of a methyl donor (S-adenosyl-L-methionine) resulted in the formation of 3-OM-L-DOPA; this was abolished by 1 microM tolcapone. The fractional outflow of intracellular L-DOPA through the luminal and abluminal cell side was not affected by the presence of intracellular 3-OM-L-DOPA. The fractional outflow of exogenous 3-OM-L-DOPA applied from the luminal cell border was similar to that observed for 3-OM-L-DOPA with origin in L-DOPA. It is concluded that RBE 4 and RBE 4B cells are endowed with the L-type amino acid transporter through which L-DOPA and 3-OM-L-DOPA can be taken up, and 3-OM-L-DOPA behaves as a competitive inhibitor for the uptake of L-DOPA. This, however, only occurs for luminal cell inward movement but not for abluminal cell outward movement of the substrates.

Amino Acids↗
PubMed2001

Targeted gene mutation approaches to the study of anxiety-like behavior in mice.

Studying the behavioral phenotypes of transgenic and gene knockout mice is a powerful means to better understand the pathophysiology of neuropsychiatric disorders and ultimately improve their treatment. This paper provides an overview of the methods and findings of studies that have tested for anxiety-related behavioral phenotypes in gene mutant mice. In the context of improving the side effect burden of benzodiazepines, gene targeting has been valuable for dissociating the functional roles (i.e., anxiolytic, sedative, amnestic) of individual GABA(A) receptor subunits. Supporting the link between abnormalities in CRH function and anxiety, CRH overexpressing transgenic mice and CRH-R2 receptor knockout mutants have displayed significantly increased anxiety-like behavior, while CRH-R1 receptor knockout mice have shown an anxiolytic-like phenotype. Consistent with an important role for the serotonergic system in anxiety, 5-HT1(A) receptor deficient mice have consistently exhibited heightened anxiety-like behavior, while the evidence from 5-HT1(B) and 5-HT2(C) deficient mice remains somewhat equivocal. Mutant mice lacking either of the monoamine degrading enzymes, MAOA or COMT, have shown a number of behavioral and neurological effects, including alterations in anxiety-like behavior. With enhanced spatial and temporal control over gene mutations, in combination with an improved battery of behavioral tests, gene mutant mice will provide an increasingly valuable tool for understanding the neural substrates of anxiety.

Animals↗
PubMed2003

Genetics of human prefrontal function.

Evolution of the prefrontal cortex was an essential precursor to civilization. During the past decade, it became increasingly obvious that human prefrontal function is under substantial genetic control. In particular, heritability studies of frontal lobe-related neuropsychological function, electrophysiology and neuroimaging have greatly improved our insight. Moreover, the first genes that are relevant for prefrontal function such as catechol-O-methyltransferase (COMT) are currently discovered. In this review, we summarize the present knowledge on the genetics of human prefrontal function. For historical reasons, we discuss the genetics of prefrontal function within the broader concept of general cognitive ability (intelligence). Special emphasis is also given to methodological concerns that need to be addressed when conducting research on the genetics of prefrontal function in humans.

Brain Chemistry↗
PubMed2000

Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphisms in patients at risk for suicide.

Genotype frequencies of functional polymorphisms in the genes encoding the serotonin transporter (5-HTT) and the enzyme catechol-O-methyltransferase (COMT) were not different in 51 suicidal inpatients compared to 51 control subjects. Within the patient group, increased hopelessness and suicide ideation were associated with homozygosity of the 5-HTT high promotor activity allele.

Adult↗
PubMed1999

cDNA cloning, expression and chromosomal localization of the mouse mitochondrial thioredoxin reductase gene(1).

Cytosolic thioredoxin (Trx) and thioredoxin reductase (TrxR) comprise a ubiquitous system that uses the reducing power of NADPH to act as a general disulfide reductase system as well as a potent antioxidant system. Human and rat mitochondria contain a complete thioredoxin system different from the one present in the cytosol. The mitochondrial system is involved in the oxidative stress protection through a mitochondrial thioredoxin-dependent peroxidase. We report here the cDNA cloning and chromosomal localization of the mouse mitochondrial thioredoxin reductase gene (TrxR2). The mouse TrxR2 cDNA encodes for a putative protein of 527 amino acid residues with a calculated molecular mass of 57 kDa, that displays high homology with the human and rat counterparts. The N-terminus of the protein displays typical features of a mitochondrial targeting sequence with absence of acidic residues and abundance of basic residues. Mouse TrxR2 also contains a stop codon in frame at the C-terminus of the protein, necessary for the incorporation of selenocysteine that is required for enzymatic activity. The typical stem-loop structure (SECIS element) that drives the incorporation of selenocysteine is identified in the 3'-UTR. Northern analysis of the mouse TrxR2 mRNA shows a similar pattern of expression with the human homologue, with higher expression in liver, heart and kidney. Finally, we have assigned the mouse TrxR2 gene to chromosome 16 mapping at 11.2 cM from the centromer and linked to the catechol-o-methyltransferase (comt) gene.

Amino Acid Sequence↗
PubMed1999

Regulation of dopamine uptake by basic fibroblast growth factor and epidermal growth factor in cultured rat astrocytes.

We examined the characteristics of dopamine (DA) uptake and its regulation by neurotrophic factors such as basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) in cultured rat astrocytes. In the presence of inhibitors of monoamine oxidase (MAO) and catechol-O-methyl-transferase (COMT), astrocytes took up DA by Na(+)-dependent and Na(+)-independent mechanisms that were sensitive to a reduction in temperature. The Na(+)-dependent and Na(+)-independent components increased linearly with increasing [3H]DA concentration (1-1000 microM), and showed no saturation. Na(+)-dependent DA uptake was significantly inhibited by ouabain, a Na(+)-K+ ATPase inhibitor. In bFGF-treated astrocytes, [3H]DA uptake increased in a time-dependent manner until 48 h, and declined after 72 h in both the presence and absence of Na+. In EGF-treated astrocytes, [3H]DA uptake increased in a time-dependent manner until 72 h in both the presence and absence of Na +. This enhancement of DA uptake induced by EGF or bFGF was significantly inhibited when the cells were cultured with actinomycin D, cycloheximide, or brefeldin A. Actinomycin D and brefeldin A also significantly inhibited the basal uptake of [3H]DA into astrocytes. These results suggest the existence of Na(+)-dependent and Na(+)-independent DA uptake in cultured rat astrocytes, and that EGF or bFGF might stimulate the expression and translocation of the extraneuronal DA transporter.

Animals↗
PubMed1976

[Purification and properties of rat kidney catechol-O-methyltransferase].

The S-adenosyl-methionine: catechol-O-methyltransferase (EC 2.1.1.6) from rat kidney was purified about 650 fold as compared with the homogenate and the result of disc electrophoresis presented. The purification involved extraction, precipitation at pH 5, ammonium sulfate fractionation, Chromatographies on Biogel 0.5 m, Ultrogel AcA 44 and DE Sephadex A 50. Affinity chromatography was tried but unsuccessful. The enzyme exhibited two pH optima at 7.9 and 9.6 with a minimum at about 8.9. The COMT had a temperature optimum of 50 degrees C, with activation energy of 23.1 Kcal/Mole between 25-35 degrees C, 18.9 Kcal/mole between 35-45 degrees C and the Q10 within the range of 25-35 degrees amounted to 3.5. The molecular weight was estimated to be 21500+/-1000 daltons from its behavior on Ultrogel AcA 44 and the pH1 determined by electrofocalisation was near 5.50. The time of half life of the best purified enzymatic extract was found to be 2 h 10 min. at -20 degrees C. At basic pH the instability of the enzyme was increased. Since O-methylation required the presence of divalent cations, our results show that apparent Michaelis constants for Mg++ and Mn++ were respectively 0.50 X 10(-3) M and 0.33 X 10(-5) M. The study of their Hill's number indicated that there was only one point of fixation on the enzyme. The Km value determined by Florini and Vestling's method were 2.5 X 10(-4) M and 11.9 X 10(-5) M for epinephrine and S-adenosyl-methionine respectively. All results were discussed with respect to other investigations.

Animals↗
PubMed2001

Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson's disease.

Levodopa is administered with dopa decarboxylase inhibitors (DDI) to prevent its peripheral degradation. This increases conversion of levodopa to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). S-adenosylmethionine (SAM), which is synthesized from adenosine triphosphate and methionine (MET), serves as methyl donor for this O-metabolisation of levodopa with resulting conversion of SAM to total homocysteine (tHcy) via S-adenosylhomocysteine (SAH). Previous studies showed augmented plasma levels of tHcy in long-term levodopa/DDI-treated patients with Parkinson's disease (PP). Objective of this study was to compare MET, SAM, levodopa, 3-OMD, tHcy and SAH in plasma of 20 levodopa/DDI treated PP and corresponding controls. A significant decrease of MET respectively SAM and an increase of tHcy appeared in PP. SAH with its short half-life did not differ. Levodopa/DDI long-term treatment contributes to altered levels of substrates of the O-methylation cycle in PP.

Aged↗
PubMed1997

Extraneuronal uptake inhibitor U-0521 decreases contractile responses in rat vas deferens.

1. The influence of catechol-O-methyltransferase inhibitor U-0521 on isotonic contraction of isolated rat vas deferens was examined to determine optimal concentration and nonspecific effects. 2. Maximum responses to (-)-epinephrine were increased at 0.4 microM and 1 microM concentrations of U-0521. Epinephrine responses were progressively decreased in the presence of higher concentrations (10 microM, 30 microM and 100 microM) of U-0521. 3. The response to the nonadrenergic agonist neurokinin A was similarly depressed in the presence of 100 microM U-0521. 4. U-0521 not only inhibits COMT, at concentrations above 1 microM it nonspecifically depresses contraction of the rat vas deferens by both adrenergic and nonadrenergic agonists.

Adrenergic alpha-Agonists↗
PubMed2000

Toxicokinetics and analytical toxicology of amphetamine-derived designer drugs ('Ecstasy').

The phase I and II metabolites of the designer drugs methylenedioxyamphetamine (MDA), R,S-methylenedioxymethamphetamine (MDMA), R,S-methylenedioxyethylamphetamine (MDE), R, S-benzodioxazolylbutanamine (BDB) and R, S-N-methyl-benzodioxazolylbutanamine (MBDB) were identified by gas chromatography-mass spectrometry (GC-MS) or liquid chromotography-mass spectrometry (LC-MS) in urine and liver microsomes of humans and rats. Two overlapping pathways could be postulated: (1) demethylenation followed by catechol-O-methyl-transferase (COMT) catalyzed methylation and/or glucuronidation/sulfatation; (2) N-dealkylation, deamination and only for MDA, MDMA, MDE oxidation to the corresponding benzoic acid derivatives conjugated with glycine. Demethylenation was mainly catalyzed by CYP2D1/6 or CYP3A2/4, but also by CYP independent mechanisms. In humans, MDMA and MBDB could also be demethylenated by CYP1A2. N-demethylation was mainly catalyzed by CYP1A2, N-deethylation by CYP3A2/4. Based on these studies, GC-MS procedures were developed for the toxicological analysis in urine and plasma. Finally, toxicokinetic parameters are reviewed.

Amphetamines↗
PubMed1999

Separation of the glucuronides of entacapone and its (Z)-isomer in urine by micellar electrokinetic capillary chromatography.

A micellar electrokinetic capillary chromatography (MECC) method was developed for the separation of the 3-O-glucuronides of entacapone and its (Z)-isomer, the two main urinary metabolites of entacapone in humans. Entacapone is a novel, potent inhibitor of catechol-O-methyltransferase (COMT) intended for use as an adjunct in the treatment of Parkinson's disease. Urine samples spiked with synthetic 3-O-glucuronides were used to study the effects of running buffer pH, composition and applied voltage on separation of the closely migrating glucuronides. The 3-O-glucuronide of nitecapone, was used as internal standard. The greatest improvement in separation was achieved by increasing the running buffer ionic concentration. Changes in pH had little effect on the separation, whereas increase in sodium dodecyl sulfate (SDS) concentration slightly improved resolution. Baseline separation and good selectivity relative to urine components were achieved by using a phosphate (25 mM)-borate (50 mM)-SDS (20 mM) running buffer, pH 7.0, in a 75 microm x 60/67 cm fused-silica capillary at 15 kV and a 335 nm cut-off filter in the UV detector. The limits of detection (LOD) at a signal-to-noise ratio of 3 were about 0.25 microg/ml (5.2 x 10(-7) M) (injection 0.5 p.s.i./8 s). The linear detection range was 2-100 microg/ml (r2>0.999). Good repeatability of injection and relative migration times were obtained.

Buffers↗
PubMed2002

Genetic modeling of estrogen metabolism as a risk factor of hormone-dependent disorders.

Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and endometrial, prostate, and breast cancer. Available data indicate that the protective effect of a later age at menarche is limited to mutant CYP 17 allele carriers. Among women with the Polycystic Ovary (PCO) syndrome, mutant CYP 17 alleles are sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for breast cancer, advanced disease stage, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase (COMT) allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to estrogen metabolising genes as strong hereditary determinants of the susceptibility to benign and malignant conditions.

Breast Neoplasms↗
PubMed2002

Dopaminergic system genes in ADHD: toward a biological hypothesis.

Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD). Several genetic association studies have been published, but so far, no DNA variants have been unequivocally demonstrated as contributing to ADHD susceptibility. Four dopamine related gene loci have been implicated, however: DAT 1, DRD 4, DBH, and DRD 5. Each of these may influence the liability of ADHD to a small degree. Notably, all are involved in signal transduction at the neuronal synapse. In this article, we investigate as candidate genes for ADHD, DNA polymorphisms at dopamine receptors, the dopamine transporter, and genes known to be involved in dopamine synthesis and metabolism. In a recent article, we confirmed the previously reported association of DAT 1 (480 bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD 5 (148 bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4 bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH (allele 2) and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD 1, DRD 2 (Taq I), DRD 3, DRD 4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH (allele 2) and a nonsignificant trend for paternal transmission for DRD 2 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses.

Adolescent↗