Biomedical subjects
K Blum
Publications and source records attributed to K Blum.
No structural mutation in the dopamine D2 receptor gene in alcoholism or schizophrenia. Analysis using denaturing gradient gel electrophoresis.
OBJECTIVE: To examine the dopamine D2 receptor (DRD2) gene coding sequences for abnormalities associated with schizophrenia or alcoholism and thereby help to resolve the controversy surrounding the reported association of alcoholism with a restriction fragment length polymorphism located close to the DRD2 gene. DESIGN: Mutational analysis of complete DRD2 gene coding sequences by denaturing gradient gel electrophoresis followed by direct nucleotide sequencing of detected variants. SETTING: Patients and controls from clinical and epidemiologic collections in the United States and Europe. PATIENTS: A total of 253 unrelated individuals, including 106 patients with schizophrenia, 113 with alcoholism, and 34 controls. For alcoholism we included patients from previously published series in which an association of illness with allele A1 was reported (Taql site 3' to the DRD2 gene) and from other published series in which nonconfirmations of this association were reported. Nearly all persons examined were white. MAIN OUTCOME MEASURES: Frequency of nonsilent variations in DRD2 gene DNA sequences in the different diagnostic groups. RESULTS: We found three infrequent DNA variants that predict altered amino acid sequence of the receptor. None of these is associated with either alcoholism or schizophrenia. CONCLUSION: No structural coding abnormalities in the DRD2 gene are present in alcoholism or schizophrenia.
Prolonged P300 latency in a neuropsychiatric population with the D2 dopamine receptor A1 allele.
The role of the dopaminergic system in P300 has been implicated and previous studies have suggested the presence of a heritable component in the genesis of P300 or P3, a late positive component of the event-related potential. In the present investigation, 155 Caucasian male and female diagnosed neuropsychiatrically-ill patients with and without comorbid drug and alcohol abuse/dependence were genotyped for the presence or absence of the A1 allele of the D2 dopamine receptor gene (DRD2). The relationship of the A1 and A2 alleles to P3 amplitude and latency was also determined. The results showed no significant difference in P3 amplitude between all groups studied with A1 and A2 allele carriers. However, we now report prolonged P3 latency in neuropsychiatrically-ill patients (with or without polysubstance abuse) with those carrying two copies of the A1 allele (homozygote) of the DRD2 gene (quadratic trend, p = 0.01). Moreover, the age-adjusted mean P3 latency in the D2A2/A2 allele group was 327.8 +/- 3.08 ms compared by ANOVA, to 360.04 +/- 4.86 ms in the D2A1/A1 group. Our work suggests an association of polymorphisms of the DRD2 gene and a biological marker previously indicated to have predictive value in vulnerability to substance abuse.
[The MR phase contrast method. Determination of blood flow velocity and flow profile of intracranial arteries].
2D-phase-contrast mapping is a MR method that allows for quantitative measurements of blood flow velocity in intracranial vessels. Using a modified FISP-Sequence with a 1.5 T MR scanner, flow studies were carried out on a phantom. Two matrix sizes (256 x 256 vs. 256 x 512) were compared. In 20 healthy volunteers blood flow velocity and profile of the basal (BA), middle cerebral (MCA), and anterior cerebral artery (ACA) were compared with the corresponding findings of transcranial Doppler (TCD) sonography. 2DPK and TCD yielded equivalent velocity data and profiles of the BA. The blood flow velocity in the MCA determined by 2DPK was lower than the TCD values. Using a 256 x 512 matrix, the acquired data were in better accordance with the TCD findings. Due to significant noise measurements of the ACA and PCA were frequently degraded.
Alcoholism and the D2 dopamine receptor gene.
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Substance abuse vulnerability and D2 receptor genes.
Dopamine systems are key to the actions of several substances. Inter-individual differences in genes encoding proteins involved in dopaminergic neurotransmission could plausibly explain some of the genetic bases for inter-individual differences in vulnerability to substance abuse. The restriction fragment length polymorphism (RFLP) markers TaqIA1 and B1 at the dopamine D2 receptor (DRD2) gene locus in Caucasians are associated with substance abuse behaviors. In most, but not all, studies of alcoholics and polysubstance abusers, these TaqIA1 and B1 gene markers are present more often in substance abusers than in control individuals. No study has identified substance abusers or controls by sampling randomly from the general population; allelic association findings could thus conceivably be confounded by RFLP differences based on ethnicity or other factors. However, meta-analyses of the data from controlled studies available to date are consistent with the proposal that DRD2 gene variants contribute to inter-individual differences in vulnerability to alcoholism and polysubstance abuse.
Allelic association of the D2 dopamine receptor gene with cocaine dependence.
The objective of the present study was to examine allelic prevalence of the D2 dopamine receptor (DRD2) gene in male cocaine-dependent (CD) Caucasian (non-Hispanic) subjects and to determine the relationship of DRD2 alleles to family history and selected behavioral measures. The prevalence of the A1 allele in CD subjects (n = 53) was 50.9%. It was significantly higher than either the 16.0% prevalence (P < 10(-4)) in non-substance abusing controls (n = 100) or the 30.9% prevalence (P < 10(-2)) in population controls (n = 265) wherein substance abusers were not excluded. Similarly, a significantly higher prevalence (P < 10(-2)) of the B1 allele was found in CD subjects (n = 52) compared with non-substance abusing controls (n = 53); 38.5% vs. 13.2%. Logistic regression analysis of CD subjects identified potent routes of cocaine use and the interaction of early deviant behaviors and parental alcoholism as significant risk factors associated with the A1 allele. The cumulative number of these three risk factors in CD subjects was positively and significantly (P < 10(-3)) related to A1 allelic prevalence. The data showing a strong association of the minor alleles (A1 and B1) of the DRD2 with cocaine dependence suggest that a gene, located on the q22-q23 region of chromosome 11, confers susceptibility to this drug disorder.
Synchrotron x-ray diffraction study of the disordering of the Ge(111) surface at high temperatures.
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Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism.
The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and non-alcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (lambda hD2G1) of the human D2 dopamine receptor gene. The binding characteristics (Kd [binding affinity] and Bmax [number of binding sites]) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted Kd was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele, in whom a high association with alcoholism was found, the Bmax was significantly reduced compared with the Bmax of subjects with the A2 allele. Moreover, a progressively reduced Bmax was found in subjects with A2/A2, A1/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.
Allelic association of human dopamine D2 receptor gene in alcoholism.
In a blinded experiment, we report the first allelic association of the dopamine D2 receptor gene in alcoholism. From 70 brain samples of alcoholics and nonalcoholics, DNA was digested with restriction endonucleases and probed with a clone that contained the entire 3' coding exon, the polyadenylation signal, and approximately 16.4 kilobases of noncoding 3' sequence of the human dopamine D2 receptor gene (lambda hD2G1). In the present samples, the presence of A1 allele of the dopamine D2 receptor gene correctly classified 77% of alcoholics, and its absence classified 72% of nonalcoholics. The polymorphic pattern of this receptor gene suggests that a gene that confers susceptibility to at least one form of alcoholism is located on the q22-q23 region of chromosome 11.
Ethanol ingestive behavior as a function of central neurotransmission.
Uncontrollable alcohol ingestive behavior has been linked to deficits of central neurotransmission. The pineal gland plays an important role in modulating ethanol intake in numerous animal species. The opioidergic (i.e. beta-endorphin, enkephalin, and dynorphin) system is involved in both the actions of alcohol and opiates, as well as craving and/or genetic predisposition towards abuse of these two agents. Furthermore, there is significant evidence to link ingestive behaviors with the ventral tegmental accumbens-hypothalamic axis, whereby the biogenic amines dopamine and serotonin are reciprocally involved. Evidence is presented which implicates the striatum and the hypothalamus as possible specific loci for regional differences between alcohol-preferring and alcohol-nonpreferring mice. We believe that photoperiod-induced alcohol ingestive behavior may involve alterations in both pineal and hypothalamic opioid peptides.
The in vitro metabolites of 2,4,6-trichlorophenol and their DNA strand breaking properties.
The carcinogenic compound 2,4,6-trichlorophenol (2,4,6-TCP) was incubated with rat liver S-9 fraction. Three metabolites were identified: 2,6-dichloro-1,4-hydroquinone (DHQ), and two isomers of hydroxypentachlorodiphenyl ether (OH-Cl5-DPE). The latter are probably products of microsomal .OH radical attack on the trichlorophenol molecule forming phenoxy free radicals. These would undergo dimerizations with other molecules present in solution. The 2,6-dichloro-1,4-semiquinone free radical was identified by ESR spectroscopy. It is formed at physiological conditions in phosphate buffer at pH 7.2 and 7.8, with a more intensive signal at the more alkaline pH. The formation is probably due to the autoxidation of the corresponding hydroquinone. Incubation of a mixture of metabolites with PM2 DNA at pH 7.2 resulted in single strand breaks. Addition of catalase and dimethylsulfoxide (DMSO) inhibited the DNA strand scission. It was concluded that reactive oxygen species (ROS), produced during the formation of the semiquinone radical, were responsible for the observed DNA damage. The significance of the ROS and the semiquinone free radical is discussed in view of the reported tumorgenicity of 2,4,6-TCP in rats and mice.
Narcotic antagonism of seizures induced by a dopamine-derived tetrahydroisoquinoline alkaloid.
This paper describes experiments designed to evaluate whether the narcotic antagonist naloxone significantly interferes with seizures induced by tetrahydroisoquinolines (TIQs). In these experiments we found that naloxone significantly reduced seizure scores induced by intra-cranially infusing mice with 50 micrograms of the dopamine-derived tetrahydroisoquinoline (TIQ) alkaloid, 6,7-dihydroxy TIQ. These findings support an opioid involvement in the actions of TIQs and may lead to further understanding of opioid-mediated novel excitatory receptors.
Alcoholism: scientific basis of a neuropsychogenetic disease.
Until recently alcoholism was regarded as being an incurable psychological problem. During the last decade a chain of research has led to a new insight into the causes and potential alleviation of alcohol craving: Recent discoveries indicate that the brain has receptor sites for naturally occurring opiate-like substances (endorphins and enkephalins) which are produced by the nervous system. Opiates such as morphine or heroin, and some of the metabolic products of alcohol (tetrahydroisoquinolines), can also attach themselves to these receptors. It has been further discovered that the craving for alcohol is related to a deficiency of the naturally occurring opiate-like substances as well as other neurotransmitter substances. This deficiency can occur genetically or as a result of prolonged stress or long-term heavy drinking. The neurochemical imbalance may be treated chemically, leading to a possible alleviation of the craving for alcohol, especially in conjunction with psychotherapeutic and counseling regimens.
Improvement of inpatient treatment of the alcoholic as a function of neurotransmitter restoration: a pilot study.
We report results of a double-blind evaluation of the nutritional supplement SAAVE for facilitating improvement in a 30-day inpatient alcohol and drug rehabilitation center. SAAVE is uniquely designed to elevate levels of enkephalin(s), serotonin, catecholamines, and GABA, which are believed to be functionally deficient in alcoholics. Twenty-two patients were studied. The SAAVE patients, as compared to the control group (a) had a lower BUD (building up to drink) score, 1 vs 2; (b) required no PRN benzodiazepines, 0% vs 94%; (c) ceased tremoring at 72 h, as compared to 96 h; and (d) had no severe depression on the MMPI, in contrast to 24% of control group. These preliminary data suggest that SAAVE is a valuable adjunct to therapy by aiding the patient's physical adjustment to a detoxified state while facilitating a more positive response to behavioral therapy.
Regional brain [Met]-enkephalin in alcohol-preferring and non-alcohol-preferring inbred strains of mice.
Scrutiny of the data from these studies reveals that the C58/J alcohol-preferring mice have significantly lower baseline methionine-enkephalin levels in both the corpus striatum and hypothalamus compared to C3H/CHRGL/2 non-alcohol-preferring mice. In other brain regions in these two strains, specifically, pituitary, amygdala, midbrain, and hippocampus, analysis of methionine-enkephalin levels did not show any significant differences. This suggests that the hypothalamus may indeed be a specific locus involved in the regulation of alcohol intake, via the molecular interaction between neuroamines, opioid peptides, as they are influenced by genetics and environment.
Alcohol and opioid peptides: neuropharmacological rationale for physical craving of alcohol.
Until recently alcoholism was regarded as an incurable psychological problem. During the last decade a chain of research has led to important hypotheses about the etiology of the physical craving of alcohol. Recent discoveries indicate that the brain has receptor sites for naturally occurring opiatelike substances (endorphins, enkephalins, and dynorphins) which are produced by the nervous system. Opiates such as morphine or heroin and some of the metabolic products of alcohol (tetrahydroisoquinolines) can also attach themselves to these receptors. It has been further discovered that the physiological craving for alcohol may be the result of a deficiency of the naturally occurring opiatelike substances as well as other neurochemical deficits (i.e., dopaminergic, GABAergic, and serotonergic). These neurochemical deficits can occur genetically or as a result of long-term heavy drinking.
Alcoholism: scientific basis and chemotherapeutic control.
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