Dopamine transporter, alcoholism and other diseases.
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Alcoholism↗
Biomedical subjects
D Goldman
Publications and source records attributed to D Goldman.
Bromocriptine in the treatment of alcoholics.
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Alcoholism↗
Adaptation of nicotinic acetylcholine receptor, myogenin, and MRF4 gene expression to long-term muscle denervation.
Muscle activity alters the expression of functionally distinct nicotinic acetylcholine receptors (nAChR) via regulation of subunit gene expression. Denervation increases the expression of all subunit genes and promotes the expression of embryonic-type (alpha 2 beta delta gamma) nAChRs, while electrical stimulation of denervated muscle prevents this induction. We have discovered that the denervation-induced increases in alpha, beta, gamma, and delta subunit gene expression do not persist in muscles that have been denervated for periods extending beyond a couple of months. However, expression of RNA encoding the epsilon-subunit remains elevated suggesting a return to expression of predominantly adult-type (alpha 2 beta delta epsilon) nAChR in long-term denervated muscles; a finding confirmed by single channel patch-clamp analysis. Since the nAChR subunit genes are regulated by the MyoD family of muscle regulatory factors, and the genes encoding these factors are also induced following short-term muscle denervation, we determined their level of expression in long-term denervated muscle. Although MyoD and myf-5 RNA levels remained elevated, myogenin and MRF4 RNAs were induced only transiently by muscle denervation. Surprisingly, Id-1, a negative regulator of transcription, was gradually induced in denervated muscle with RNA levels peaking about two months after denervation. It is likely that this maintained level of increased Id expression, in conjunction with the returning levels of myogenin and MRF4 expression, account for the reduced level of embryonic receptors in long-term denervated muscle. These changing patterns of gene expression may have important consequences for the ability of muscle to recover function after denervation.
Adaptation, Physiological↗
Identifying alcoholism vulnerability alleles.
Identification of vulnerability alleles is one starting point for elucidating the web of interactions leading to alcoholism so that treatment and prevention can be improved. Heritability studies indicate that vulnerability alleles exist. Two molecular approaches for identifying them, direct analysis of candidate genes and genetic linkage, are highlighted in this review. Methodological problems that have been partially addressed and limitations for the applicability of the genetic findings are discussed.
Alcoholism↗
Mitochondrial aldehyde dehydrogenase polymorphism in Asian and American Indian populations: detection of new ALDH2 alleles.
Genetic deficiency of the mitochondrial aldehyde dehydrogenase (ALDH2) is frequent in Asian peoples where it is an important factor negatively regulating drinking behavior. To obtain additional information on gene geography of known ALDH2 alleles, and look for new variants, ALDH2 genes were evaluated in a Chinese population from Taiwan, a Yakut population of Siberia, and in five North American Indian populations. A novel approach based on a single-strand conformation polymorphism assay, and polymerase chain reaction-directed mutagenesis was developed for genotyping. In the Taiwan Chinese population, the ALDH2(2) allele frequency was 0.319 +/- 0.025, and this allele was not detected in the Yakut population nor in the five North American Indian populations. However, a new allele, ALDH2(3), was detected in Pima Indians at a frequency of 0.044 +/- 0.022, and this allele was also observed in 1 of 49 Pueblo samples. ALDH2(3) is a silent transition 1464 G-->A, and it possibly has a wide distribution among North American Indians. A new subtype of the ALDH2(2) allele, designated as ALDH2(2Taiwan), was found in 1 of 174 Chinese from Taiwan. ALDH2(2Taiwan) is characterized by two G-->A transitions at bases 1486 and 1510, resulting in Glu-->Lys substitutions at both the 479 and 487 positions. Thus, this second nonconservative ALDH2 substitution occurs within the sequence of the already inactive ALDH2(2) allele.
Alcoholism↗
Postdischarge medication compliance of inpatients converted from an oral to a depot neuroleptic regimen.
OBJECTIVE: This preliminary study assessed the effects on outpatient medication compliance of converting inpatients with schizophrenia from oral to depot neuroleptic medication. METHODS: Subjects consisted of 93 neuroleptic-responsive inpatients with schizophrenia from three New York City hospitals who were part of a one-year prospective longitudinal study of medication compliance. Forty patients were converted to depot neuroleptic medication while hospitalized; the other 53 remained on oral medication. Symptoms, side effects, and medication compliance of the two groups were compared at one, six, and 12 months postdischarge. RESULTS: Inpatients converted to depot medication had significantly better compliance at one month postdischarge. Differences in demographic characteristics, symptoms, hospital site, and baseline attitudes toward medication did not account for this finding. The initial positive effect on compliance waned, and no significant between-group differences in compliance were found at six and 12 months postdischarge. CONCLUSIONS: Conversion to depot medication before hospital discharge may facilitate medication compliance during transition to outpatient treatment, but other interventions are needed to maintain compliance over time.
Administration, Oral↗
Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence.
The findings of a series of studies by the authors support the idea that most impulsive offenders who have a tendency to behave aggressively while intoxicated have a low brain serotonin turnover rate. The impulsive violent offenders with the lowest CSF 5-HIAA concentrations have diurnal activity rhythm disturbances, and are also prone to hypoglycemia after an oral glucose challenge. Low CSF 5-HIAA combined with hyoglycemic tendency also predicts future violence under the influence of alcohol. Sons of alcoholic fathers, who have committed violent crimes, have very low CSF 5-HIAA concentrations. Vagal tone does not correlate significantly with CSF 5-HIAA but correlates with enhanced insulin secretion, which is most prominent in subjects with intermittent explosive disorder. A polymorphism of tryptophan hydroxylase (TPH) gene is associated with low CSF 5-HIAA and a history of suicide attempts.
Alcoholism↗
Elevation of maternal alpha-fetoprotein in systemic lupus erythematosus: a controlled study.
OBJECTIVE: To determine if maternal alpha fetoprotein (AFP) is elevated in lupus pregnancy and, if so, whether it is associated with treatment or outcome. METHODS: Maternal serum AFP values were obtained once during Weeks 16.3 to 31.7 in 54 pregnancies followed prospectively. AFP was measured by the Maryland State Health Department, who reported the AFP level and a corrected value, multiple of the median (AFP MOM), adjusted for weight, gestational age, and insulin dependent diabetes. Controls were 1001 consecutive samples measured by the same laboratory. RESULTS: AFP MOM was higher in lupus pregnancies (1.425 +/- 0.73 vs 1.169 +/- 0.50, p = 0.001), as were the unadjusted AFP levels (lupus 68.26 +/- 42.2, control 52.49 +/- 27.25, p = 0.001). Of lupus pregnancies 7.4 vs 2.6% of control pregnancies had an abnormal AFP MOM (p = 0.06). The 4 patients with abnormal AFP-MOM, using the 2.3 cutoff, were taking more prednisone (27.25 +/- 18.54 mg vs 10.85 +/- 12.29 mg, p = 0.02), were more likely to have delivered preterm (31.50 +/- 36.31 weeks, p = 0.02), and were more likely to have a high anticardiolipin (aCL) antibody during the pregnancy (p = 0.03). CONCLUSION: AFP is higher in lupus than in control pregnancies, without any increase in neural tube or other birth defects. An abnormal maternal serum AFP level is associated with higher prednisone dose, preterm delivery and aCL. Patients and obstetricians need to be aware that an elevated maternal AFP in lupus pregnancy is not necessarily due to a birth defect, and may be predictive of preterm delivery.
Adult↗
Trans-synaptic regulation of NMDA receptor RNAs during optic nerve regeneration.
A goldfish NMDA receptor (NMDAR) cDNA was used to analyze NMDAR RNA expression during optic nerve regeneration. Following crush of the optic nerve, NMDAR RNA levels initially decrease and then increase in retinal ganglion cells. This latter increase corresponds with the time when ganglion cell axons are forming stable connections with their targets in the optic tectum. NMDAR RNA stability assays indicate that the increase in this RNA is largely a result of increased NMDAR gene expression. This increase requires return of electrical activity in the regenerating axons, interaction between ganglion cell axons and their targets in the optic tectum, and functional NMDARs in the postsynaptic tectal cells. These requirements for induction of presynaptic NMDAR RNA are similar to those proposed for synapse stabilization during development and regeneration of the visual system and during long-term potentiation (LTP) in the hippocampus.
Amino Acid Sequence↗
Candidate genes in alcoholism.
Individual alleles identified by candidate gene analysis have been shown to profoundly influence certain complex behavioral syndromes including vulnerability to alcoholism. The alcohol and aldehyde dehydrogenase polymorphisms, ADH2(2) and ALDH2(2), respectively, are associated with lower vulnerability to alcoholism both in the Orient and also in North America among populations of Taiwanese and Koreans who have immigrated there. Protein structural variants have recently been identified for a series of genes involved in dopamine and serotonin function. Three dopamine receptors exhibit such structural variants, and these include the DRD2 dopamine receptor, which has three relatively rare amino acid substitutions. Structural polymorphisms were detected in five serotonin receptors (5HT1A, 5HT1Db, 5HT2A, 5HT2C, and 5HT7). Association studies between neurotransmitter gene variants and alcoholism are at an earlier stage than with ADH2(2)/ALDH2(2), but results are thus far negative (dopamine DRD4 receptor), equivocal (dopamine DRD2 receptor), or preliminary (tryptophan hydroxylase, 5HT2C and 5HT1Db).
Alcoholism↗
Protein-tyrosine phosphatases specifically regulate muscle adult-type nicotinic acetylcholine receptor gene expression.
Innervation of skeletal muscles results in expression of adult-type nicotinic acetylcholine receptors (alpha 2 beta epsilon delta) beneath the neuromuscular junction. This local expression is largely a result of selective induction of adult-type nicotinic acetylcholine receptor (nAChR) genes in endplate-associated myonuclei. The molecular mechanism by which the nerve induces gene expression in these nuclei is not known. We have shown previously that ionophore-induced calcium influx across the plasma membrane preferentially decreases expression from the adult-type specific nAChR epsilon-subunit gene (Walke, W., Staple, J., Adams, L., Gnegy, M., Chahine, K., and Goldman, D. (1994) J. Biol. Chem. 269, 19447-19456). Here we provide evidence that the genes encoding adult-type nAChRs are specifically regulated by protein-tyrosine phosphatase activity. Orthovanadate, a specific protein-tyrosine phosphatase inhibitor, caused increased expression of the epsilon-subunit gene in rat primary myotubes and was able to completely block the suppressive effects of increased calcium influx on epsilon-subunit RNA expression. Overexpression of protein-tyrosine phosphatases selectively decreased expression from the adult-type nAChR genes with no effect on the embryonic-type specific gamma-subunit gene. These results demonstrate that protein-tyrosine phosphatases regulate mammalian adult-type nAChR gene expression and suggest a mechanism by which muscle innervation selectively regulates gene expression in endplate-associated myonuclei.
Aging↗
Calcium-dependent regulation of rat and chick muscle nicotinic acetylcholine receptor (nAChR) gene expression.
Muscle depolarization leads to decreased expression of nicotinic acetylcholine receptor (nAChR) genes in extrajunctional regions of the muscle fiber with little effect on their expression at the neuromuscular junction (NMJ). Depolarization-dependent decreases in nAChR gene expression have been linked to a cAMP-dependent signaling system in rat (Chahine, K. G., Baracchini, E., and Goldman, D. (1993) J. Biol. Chem. 2893-2898), and a calcium-dependent protein kinase C (PKC) signaling system in chick (Klarsfeld, A., Laufer, R., Fontaine, B., Devillers-Thiery, A., Bubreuil, C., and Changeux, J. P. (1989) Neuron 2, 1229-1236). We report here on experiments investigating the role of calcium and PKC in regulating rat muscle nAChR gene expression. These studies indicate that depolarization-dependent regulation of rat muscle nAChR gene expression is independent of PKC activity. However, these genes are regulated by a calcium-dependent signal transduction system. Calcium influx across the plasma membrane decreases nAChR gene expression in inactive rat myotubes. Surprisingly, this influx of extracellular calcium is most effective at reducing nAChR epsilon-subunit gene expression. We also provide evidence that a similar signal transduction system is capable of regulating nAChR gene expression in chick muscle. Based on these data we propose that calcium, in addition to mediating depolarization-dependent regulation of nAChR expression, may also participate in restricting their expression to the neuromuscular junctions of adult muscle fibers.
Animals↗
Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism.
BACKGROUND: To examine whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme in the biosynthesis of serotonin, may be a factor influencing serotonin turnover and behaviors controlled by serotonin. METHODS: Using a polymerase chain reaction-based method, TPH genotype was determined in DNA samples from 56 impulsive and 14 nonimpulsive, alcoholic, violent offenders and 20 healthy volunteers. RESULTS: In the behaviorally extreme impulsive group, we observed a significant association between TPH genotype and cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) concentration. No association of TPH genotype with impulsive behavior was detected. The polymorphism was also associated with a history of suicide attempts in all violent offenders, independent of impulsivity status and cerebrospinal fluid 5-HIAA concentration. CONCLUSION: In some individuals, a genetic variant of the TPH gene may influence 5-HIAA concentration in the cerebrospinal fluid and predisposition to suicidal behavior.
Adult↗
Serotonin, violent behavior and alcohol.
At the NIAAA intramural research program, in collaboration with investigators at the Department of Psychiatry, University of Helsinki, we have mounted an extensive research program on early onset male alcoholism. A central serotonergic deficit is common among these patients. This finding has led to behavioral, biochemical, physiological and molecular genetic studies on the serotonin system in early onset, antisocial and violent male alcoholics and in appropriate control populations. The results of the studies completed by the fall of 1993 are summarized in this communication.
Age Factors↗
Phylogenetic reconstruction of South American felids defined by protein electrophoresis.
Phylogenetic associations among six closely related South American felid species were defined by changes in protein-encoding gene loci. We analyzed proteins isolated from skin fibroblasts using two-dimensional electrophoresis and allozymes extracted from blood cells. Genotypes were determined for multiple individuals of ocelot, margay, tigrina, Geoffroy's cat, kodkod, and pampas cat at 548 loci resolved by two-dimensional electrophoresis and 44 allozyme loci. Phenograms were constructed using the methods of Fitch-Margoliash and neighbor-joining on a matrix of Nei's unbiased genetic distances for all pairs of species. Results of a relative-rate test indicate changes in two-dimensional electrophoresis data are constant among all South American felids with respect to a hyena outgroup. Allelic frequencies were transformed to discrete character states for maximum parsimony analysis. Phylogenetic reconstruction indicates a major split occurred approximately 5-6 million years ago, leading to three groups within the ocelot lineage. The earliest divergence led to Leopardus tigrina, followed by a split between an ancestor of an unresolved trichotomy of three species (Oncifelis guigna, O. geoffroyi, and Lynchailuris colocolo) and a recent common ancestor of Leopardus pardalis and L. wiedii. The results suggest that modern South American felids are monophyletic and evolved rapidly after the formation of the Panama land bridge between North and South America.
Alleles↗
T helper cell dysfunction in systemic lupus erythematosus (SLE): relation to disease activity.
Patients with systemic lupus erythematosus (SLE) are known to have defects in both humoral and cellular immunity. The significance of defective T cell-mediated immunity and its relationship to disease activity have not been clearly established. We studied in vitro T helper cell (Th) function in 150 SLE outpatients and correlated Th function with validated measures of disease activity. Interleukin 2 (IL-2) production by peripheral blood mononuclear cells (PBMC) was measured after stimulation with the recall antigens influenza A virus (FLU) and tetanus toxoid (TET), irradiated allogeneic peripheral blood mononuclear cells (ALLO), and phytohemagglutinin (PHA). We observed three patterns of Th response: (1) 76 of 150 (50%) of patients responded to the recall antigens FLU and/or TET, ALLO, and PHA; (2) 62 of 150 (42%) of patients did not respond to recall antigens but responded to ALLO and PHA; and (3) 12 of 150 (8%) of patients did not respond to either recall antigens or ALLO antigens. This diminished T cell function was correlated with higher disease activity as measured by four scales of clinical activity, such that individuals who exhibited more in vitro immune dysfunction presented with significant increases in their clinical activity indices. The alterations in T cell function could not be accounted for by medication doses alone. Thus, SLE patients have multiple distinct defects at the level of the Th cell which are associated with clinical measures of disease activity.
Adult↗
Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis.
PURPOSE: To determine the effect of prednisone dose and hydroxychloroquine dose on the coronary artery disease risk factors serum cholesterol level, mean arterial blood pressure, and weight in patients with systemic lupus erythematosus. PATIENTS AND METHODS: A longitudinal cohort study of 264 patients with systemic lupus erythematosus was conducted. For all patients in the cohort, serum cholesterol, mean arterial pressure, weight, prednisone dose, hydroxychloroquine dose, and other potential confounding variables were recorded at each visit. Regression analysis appropriate for longitudinal data was used to assess the effect of prednisone on serum cholesterol and mean arterial pressure. To assess the effect of prednisone on weight, patients' weights were compared 90 days before and after a 10-mg or 20-mg increase in prednisone. RESULTS: A total of 3,027 patient visits were analyzed. In the regression model for serum cholesterol, a change in prednisone dose of 10 mg was associated with a change in cholesterol of 7.5 +/- 1.46 (SE) mg% after adjustment for the other significant variables in the model, including sex, race, hydroxychloroquine dose, and proteinuria. In the regression model for hydroxychloroquine, the 200-mg and the 400-mg dose were both associated with lower serum cholesterol (8.9 +/- 3.44 SE mg%). In the regression model for mean arterial blood pressure, a 10-mg change in prednisone dose led to a change in mean arterial blood pressure of 1.1 mm Hg after adjustment for age, weight, and antihypertensive drug use. A 10-mg increase in prednisone dose was associated with a mean weight change of 5.50 +/- 1.23 (SE) lb. CONCLUSIONS: Changes in prednisone dose led to definable changes in risk factors for coronary artery disease, even after adjustment for other variables known to affect these risk factors. According to longitudinal regression analysis, hydroxychloroquine therapy was associated with lower serum cholesterol.
Adult↗
Rating of medication influences (ROMI) scale in schizophrenia.
Noncompliance with neuroleptic treatment is a major barrier to delivery of effective treatment for schizophrenia outpatients. This article describes the development of a standardized measure for the assessment of attitudinal and behavioral factors influencing patient compliance with neuroleptic treatment. The Rating of Medication Influences (ROMI) scale was developed as part of a longitudinal study of neuroleptic noncompliance in schizophrenia and administered to 115 discharged schizophrenia outpatients. Analyses of the following were conducted to assess the scale's psychometric properties: (1) interrater reliability, (2) internal consistency, (3) principal components, (4) correlation with other subjective measures, and (5) correlation with independent family reports. Most (95%) of the ROMI patient-report items were reliable, whereas rater-judgment items were not reliable. The rater section was dropped. A principal components analysis of the reliable patient-report items yielded three subscales related to compliance (Prevention, Influence of Others, and Medication Affinity) and five subscales related to noncompliance (Denial/Dysphoria, Logistical Problems, Rejection of Label, Family Influence, and Negative Therapeutic Alliance). There were significant correlations between these subscales, and independently obtained family-report ROMI items were significant. The Denial/Dysphoria subscale correlated strongly with two other published measures of dysphoric response to neuroleptics, whereas the other noncompliance subscales did not. The ROMI is a reliable and valid instrument that can be used to assess the patient's subjective reasons for medication compliance and non-compliance. The subscale findings suggest that the ROMI provides a more comprehensive data base for patient-reported compliance attitudes than the other available subjective measures. Indications for use of the ROMI and other subjective measures of neuroleptic response are reviewed.
Adult↗